2″ oxo-voruscharin and derivatives thereof

ABSTRACT

2″ oxo-voruscharin compound and derivatives thereof are disclosed as well as pharmaceutical compositions which include 2″ oxo-voruscharin compound or derivatives thereof. The disclosed 2″ oxo-voruscharin compound and its derivatives are useful for cancer treatment. Methods of treating cancer using the disclosed compounds are also disclosed.

This application is the U.S. National Phase under 35 U.S.C. § 371 ofInternational Application PCT/EP2003/011194, filed Oct. 9, 2003, whichclaims priority of U.S. provisional application No. 60/420,067, filedOct. 21, 2002 and EP 02447192.2, filed Oct. 9, 2002.

FIELD OF THE INVENTION

The present invention relates to novel 2″ oxo-voruscharin andderivatives thereof. In addition, the present invention relates topharmaceutical compositions comprising the novel 2″ oxo-voruscharin orderivatives. The present invention further relates to the use of the 2″oxo-voruscharin and derivatives as a medicament and in the preparationof a medicament for treating cancer. The present invention also relatesto a method of treating cancer.

BACKGROUND OF THE INVENTION

Plants of the family Asclepiadaceae are known to be extremely poisonous.A well-known representative of the Asclepiadaceae is Calotropis procera.Extracts from Calotropis procera plants have traditionally been used asan abortifacient, for infanticide, for rheumatic pain and to produce apurgative. The plant is poisonous, but has been used in small amountsfor folk remedies for various ailments, and the plant continues to bestudied for anti-coagulant and anti-cancer properties. The stems,flowers and leaves of Calotropis procera plants are known to containcertain compounds known as cardenolides. Examples of cardenolideglycosides found in C. procera include asclepin, voruscharin, uscharin,uscharidin, calotropin, calactin, calotoxin, calotropagenin anduzarigenin. Recently, cytotoxic activity has been attributed to thesecardenolide glycosides, and they are exploited in human therapies fortreating cardiac insufficiencies.

It has been described that the cardenolide uscharin is particularlyuseful for medical purposes. Uscharin has been isolated and its chemicalstructure was determined (structure I).

Compositions comprising uscharin or salts thereof have been reported tobe usable for treatment of medical conditions related to cellproliferation. For example, U.S. Pat. No. 6,342,490 and WO-9852562 bothdescribe compositions comprising uscharin or salts thereof and the useof uscharin to combat cell proliferation, e.g. in the treatment ofcancer.

Some of the known cardenolide glycosides, f.e. calotropin anduzarigenin, are cytotoxic for cell cultures but are not mentioned toshow in vivo tumor-inhibiting activity. Also uscharin has been shown tohave some cytotoxic activity on tumor cells in vitro. In addition,uscharin was also described to have in vivo tumor-inhibiting effects, asfor instance described in U.S. Pat. No. 6,342,490. Derivatives ofuscharin have not been reported so far to be useful for medicalapplications.

Cheung et al. (1983; J. Chem. Soc. Perkin Transactions 1: Organic andbio-organic chemistry (1971-1999) (12) 2827-235) disclose thestereochemistry of cardenolide glycosides of Asclepiadaceae including19-deoxyuscharin, uscharin and voruscharin.

In U.S. Pat. No. 5,645,988 methods of identifying drugs with selectiveeffects against cancer cells are presented. The drug indicated with650362 shows some similarity with uscharin.

It is a general object of the present invention to provide novelcardenolide glycosides, which have a cytotoxic activity. It is anothergeneral object of the present invention to provide novel cardenolideglycosides, which can be exploited in medical applications.

SUMMARY

In a first aspect, the present invention relates to a compound of theformula I or a pharmaceutically acceptable salt thereof,

-   -   wherein R¹ is selected from the group comprising hydrogen,        alkyl, alkenyl, alkynyl, alkyloxy, alkyloxyalkyl,        alkylthioalkyl, alkyloxycarbonyl, alkylthiocarbonyl, alkanoyl,        cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl,        cycloalkylthiocarbonyl, cycloalkylalkoxycarbonyl,        cycloalkylalkoxythiocarbonyl, cycloalkylthioalkyl,        alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl,        cycloalkylcarbonyloxyalkyl, silyloxyalkyl, aralkyl, arylalkenyl,        arylcarbonyl, aryloxycarbonyl, arylthiocarbonyl,        aralkoxycarbonyl, arylalkylthiocarbonyl, aryloxyalkyl,        arylthioalkyl, haloalkyl, hydroxyalkyl, aralkanoyl, aroyl,        aryloxycarbonylalkyl, aryloxyalkanoyl, carboxyl, formyl,        alkenylcarbonyl, alkynylcarbonyl, Het¹, Het¹alkyl, Het¹oxyalkyl,        Het¹aryl, Het¹aralkyl, Het¹cycloalkyl, Het¹carbonyl,        Het¹alkoxycarbonyl, Het¹alkylthiocarbonyl, Het¹oxycarbonyl,        Het¹thiocarbonyl, Het¹alkanoyl, Het¹aralkanoyl,        Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,        Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹aroyl,        Het¹oxyalkylcarbonyl, Het¹alkyloxyalkylcarbonyl,        Het¹aryloxyalkylcarbonyl, Het¹carbonyloxyalkyl,        Het¹alkylcarbonyloxyalkyl, Het¹aralkylcarbonyloxyalkyl,        Het²alkyl; Het²oxyalkyl, Het²alkyloxyalkyl, Het²aralkyl,        Het²carbonyl, Het²oxycarbonyl, Het²thiocarbonyl, Het²alkanoyl,        Het²alkylthiocarbonyl, Het²alkoxycarbonyl, Het²aralkanoyl,        Het²aralkoxycarbonyl, Het²aryloxycarbonyl, Het²aroyl,        Het²aryloxyalkyl, Het²arylthioalkyl, Het²oxyalkylcarbonyl,        Het²alkyloxyalkylcarbonyl, Het²aryloxyalkylcarbonyl,        Het²carbonyloxyalkyl, Het²alkylcarbonyloxyalkyl,        Het²aralkylcarbonyloxyalkyl, cyano, aminocarbonyl,        aminoalkanoyl, aminoalkyl, CR⁶═NR⁷ or CR⁶═N(OR⁷), with R⁶ and R⁷        being independently selected from the group comprising hydrogen,        hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,        alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino,        arylcarbonylamino, alkylthiocarbonylamino and        arylthiocarbonylamino;    -   wherein R² and R³ are independently selected from the group        comprising hydroxyl, alkyloxy, alkylsilyloxy, arylsilyloxy,        alkyloxyalkyloxy, cycloalkyloxy cycloalkylalkyloxy, aralkyloxy,        aryloxyalkyloxy, silyloxy, alkylcarbonyloxy, arylcarbonyloxy,        cycloalkylcarbonyloxy, haloalkyloxy, hydroxyalkyloxy,        aralkanoyloxy, aroyloxy, aryloxycarbonylalkyloxy, formyloxy,        Het¹alkyloxy, Het¹oxy, Het¹oxyalkyloxy, Het¹aryloxy,        Het¹aralkyloxy, Het¹cycloalkyloxy, Het¹carbonyloxy,        Het¹oxycarbonyloxy, Het¹alkanoyloxy, Het¹aralkanoyloxy,        Het¹aryloxyalkyloxy, Het¹aroyl, Het²oxy, Het²alkyloxy;        Het²oxyalkyloxy, Het²aralkyloxy, Het²cycloalkyloxy,        Het²alkanoyloxy, Het²aralkanoyloxy, Het²carbonyloxyl,        Het²aryloxy, Het²aryloxyalkyloxy,    -   wherein R¹ R² and R³ are optionally substituted by one or more        substituents independently selected from the group comprising        alkyl, aralkyl, aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl,        carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl,        aminosulfonyl, alkylS(═O)_(t), hydroxy, cyano, halogen or amino        optionally mono- or disubstituted wherein the substituents are        independently selected from the group comprising alkyl, aryl,        aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,        arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,        arylaminoalkoxy, aralkylamino, aryloxyalkylamino,        arylaminoalkylamino, aryithioalkoxy, arylthioalkylamino,        aralkylthio, aryloxyalkylthio, arylaminoalkylthio,        arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl,        Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,        Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio,        Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸,        SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN, CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹),        N₃, NO₂, NR⁸R⁹, N(OH)R⁸, C(O)R⁸, C(S)R⁸, CO₂R⁸, C(O)SR⁸,        C(O)NR⁸R⁹, C(S)NR⁸R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸, NR⁸C(O)R⁹,        NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,        and NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹,        N(OH)C(S)NR⁸R⁹, NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹,        NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, P(O)(OR⁸)(OR⁹),    -   with t being an integer between 1 and 2, and R⁸ R⁹ and R¹⁰ being        each independently selected from the group comprising hydrogen,        hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,        alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino,        arylcarbonylamino, alkylthiocarbonylamino and        arylthiocarbonylamino;    -   wherein R⁴ is selected from the group comprising hydrogen, oxo,        is replaced by a double bond between the N atom and the C carbon        atom on the N-containing heterocyclic ring of formula I;        hydroxyl, alkyl, alkenyl, alkynyl, alkanediyl, alkyloxy,        alklylthio, alkylamino, alkyloxyalkyl, arylcarbonylalkyl,        alkylcarbonylalkyl, alkanoyl, cycloalkylcarbonylalkyl,        cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkylamino,        cycloalkylalkyl, cycloalkylalkanoyl, aryl, aralkyl, arylalkenyl,        arylcarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,        aryloxyalkyl, haloalkyloxy, haloalkylthio, haloalkylamino,        hydroxyalkyl, aralkanoyl, aryloxycarbonylalkyl, aryloxyalkanoyl,        Het¹, Het¹alkyl, Het¹oxy, Het¹oxyalkyl, Het¹aryl, Het¹aralkyl,        Het¹cycloalkyl, Het¹aryloxyalkyl, Het¹aroyl, Het², Het²oxy,        Het²alkyl; Het²oxyalkyl, Het²aralkyl, Het²cycloalkyl, Het²aryl,        Het²alkanoyl, Het²aralkanoyl, Het²aroyl, Het²aryloxyalkyl,        aminocarbonyl, aminoalkanoyl, aminoalkyl, optionally substituted        by one or more substituents independently selected from the        group comprising alkyl, aralkyl, aryl, Het¹, Het², cycloalkyl,        alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or        di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,        cyano, halogen or amino optionally mono- or disubstituted        wherein the substituents are independently selected from the        group comprising alkyl, aryl, aralkyl, aryloxy, arylamino,        arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio,        alkoxy, aryloxyalkoxy, arylaminoalkoxy, aralkylamino,        aryloxyalkylamino, arylaminoalkylamino, arylthioalkoxy,        arylthioalkylamino, aralkylthio, aryloxyalkylthio,        arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,        cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino,        Het²amino, Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio,        Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR¹¹, SR¹¹,        SO₂NR¹¹R¹², SO₂N(OH)R¹¹, CN, CR¹¹═NR¹², S(O)R¹¹, SO₂R¹¹,        CR¹¹═N(OR¹²), N₃, NO₂, NR¹¹R¹², N(OH)R¹¹, C(O)R¹¹, C(S)R¹¹,        CO₂R¹¹, C(O)SR¹¹, C(O)NR¹¹R¹², C(S)NR¹¹R¹², C(O)N(OH)R¹²,        C(S)N(OH)R¹¹, NR¹¹C(O)R¹², NR¹¹C(S)R¹², N(OH)C(O)R¹²,        N(OH)C(S)R¹¹, NR¹¹CO₂R¹², NR¹¹C(O)NR¹²R¹³, and NR¹¹C(S)NR¹²R¹³,        N(OH)CO₂R¹¹, NR¹¹C(O)SR¹², N(OH)C(O)NR¹¹R¹², N(OH)C(S)NR¹¹R¹²,        NR¹¹C(O)N(OH)R¹², NR¹¹C(S)N(OH)R¹², NR¹¹SO₂R¹², NHSO₂NR¹¹R¹²,        NR¹¹SO₂NHR¹², P(O)(OR¹¹)(OR¹²), wherein t is an integer between        1 and 2, R¹¹, R¹² and R¹³ are each independently selected from        the group comprising hydrogen, alkyl, alkenyl, and alkynyl; and    -   wherein R⁵ is selected from the group comprising hydrogen, oxo,        hydroxyl, alkyl, alkenyl, alkynyl, alkanediyl, alkyloxy,        alkyloxyalkyl, arylcarbonylalkyl, alkylcarbonylalkyl, alkanoyl,        cycloalkylcarbonylalkyl, cycloalkyl, cycloalkylalkyl,        cycloalkylalkanoyl, aryl, aralkyl, arylalkenyl, arylcarbonyloxy,        aryloxycarbonyloxy, aralkoxycarbonyloxy, aryloxyalkyl,        haloalkyl, hydroxyalkyl, aralkanoyl, aryloxycarbonylalkyl,        aryloxyalkanoyl, Het¹, Het¹alkyl, Het¹oxy, Het¹oxyalkyl,        Het¹aryl, Het¹aralkyl, Het¹cycloalkyl, Het¹aryloxyalkyl,        Het¹aroyl, Het², Het²oxy, Het²alkyl; Het²oxyalkyl, Het²aralkyl,        Het²cycloalkyl, Het²aryl, Het²alkanoyl, Het²aralkanoyl,        Het²aroyl, Het²aryloxyalkyl, aminocarbonyl, aminoalkanoyl,        aminoalkyl, optionally substituted by one or more substituents        independently selected from the group comprising alkyl, aralkyl,        aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,        aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,        alkylS(═O)_(t), hydroxy, cyano, halogen or amino optionally        mono- or disubstituted wherein the substituents are        independently selected from the group comprising alkyl, aryl,        aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,        arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,        aylaminoalkoxy, aralkylamino, aryloxyalkylamino,        arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino,        aralkylthio, aryloxyalkylthio, arylaminoalkylthio,        arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl,        Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,        Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio,        Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR¹¹, SR¹¹,        SO₂NR¹¹R¹², SO₂N(OH)R¹¹, CN, CR¹¹═NR¹², S(O)R¹¹, SO₂R¹¹,        CR¹¹═N(OR¹²), N₃, NO₂, NR¹¹R¹², N(OH)R¹¹, C(O)R¹¹, C(S)R¹¹,        CO₂R¹¹, C(O)SR¹¹, C(O)NR¹¹R¹², C(S)NR¹¹R¹², C(O)N(OH)R¹²,        C(S)N(OH)R¹¹, NR¹¹C(O)R¹², NR¹¹C(S)R¹², N(OH)C(O)R¹²,        N(OH)C(S)R¹¹, NR¹¹CO₂R¹², NR¹¹C(O)NR¹²R¹³, and NR¹¹C(S)NR¹²R¹³,        N(OH)CO₂R¹¹, NR¹¹C(O)SR¹², N(OH)C(O)NR¹¹R¹², N(OH)C(S)NR¹¹R¹²,        NR¹¹C(O)N(OH)R¹², NR¹¹C(S)N(OH)R¹², NR¹¹SO₂R¹², NHSO₂NR¹¹R¹²,        NR¹¹SO₂NHR¹², P(O)(OR¹¹)(OR¹²), wherein t is an integer between        1 and 2, R¹¹, R¹² and R¹³ are each independently selected from        the group comprising hydrogen, alkyl, alkenyl, and alkynyl.

In an embodiment, the present invention relates to a compound of theformula I, wherein R¹ is selected from the group comprising alkyl,alkenyl, alkynyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl,alkyloxycarbonyl, alkylthiocarbonyl, alkanoyl, cycloalkylalkyl,cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylthiocarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkoxy thiocarbonyl,cycloalkylthioalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl,cycloalkylcarbonyloxyalkyl, silyloxyalkyl, aralkyl, arylalkenyl,arylcarbonyl, aryloxycarbonyl, arylthiocarbonyl, aralkoxycarbonyl,arylalkylthiocarbonyl, aryloxyalkyl, arylthioalkyl, haloalkyl,hydroxyalkyl, aralkanoyl, aroyl, aryloxycarbonylalkyl, aryloxyalkanoyl,carboxyl, formyl, alkenylcarbonyl, alkynylcarbonyl, Het¹, Het¹alkyl,Het¹oxyalkyl, Het¹aryl, Het¹aralkyl, Het¹cycloalkyl, Het¹carbonyl,Het¹alkoxycarbonyl, Het¹alkylthiocarbonyl, Het¹oxycarbonyl,Het¹thiocarbonyl, Het¹alkanoyl, Het¹aralkanoyl, Het¹aryloxyalkyl,Het¹alkyloxyalkyl, Het¹arylthioalkyl, Het¹aryloxycarbonyl,Het¹aralkoxycarbonyl, Het¹aroyl, Het¹oxyalkylcarbonyl,Het¹alkyloxyalkylcarbonyl, Het¹aryloxyalkylcarbonyl,Het¹carbonyloxyalkyl, Het¹alkylcarbonyloxyalkyl,Het¹aralkylcarbonyloxyalkyl, Het²alkyl; Het²oxyalkyl, Het²alkyloxyalkyl,Het²aralkyl, Het²carbonyl, Het²oxycarbonyl, Het²thiocarbonyl,Het²alkanoyl, Het²alkylthiocarbonyl, Het²alkoxycarbonyl, Het²aralkanoyl,Het²aralkoxycarbonyl, Het²aryloxycarbonyl, Het²aroyl, Het²aryloxyalkyl,Het²arylthioalkyl, Het²oxyalkylcarbonyl, Het²alkyloxyalkylcarbonyl,Het²aryloxyalkylcarbonyl, Het²carbonyloxyalkyl,Het²alkylcarbonyloxyalkyl, Het²aralkylcarbonyloxyalkyl, cyano,aminocarbonyl, aminoalkanoyl, aminoalkyl, CR⁶═NR⁷ or CR⁶═N(OR⁷)

-   -   with R⁶ and R⁷ being independently selected from the group        comprising hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,        Het¹aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl,        alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino        and arylthiocarbonylamino;    -   wherein R² and R³ are independently selected from the group        comprising hydroxyl, alkyloxy, alkylsilyloxy, arylsilyloxy,        alkyloxyalkyloxy, cycloalkyloxy cycloalkylalkyloxy, aralkyloxy,        aryloxyalkyloxy, silyloxy, alkylcarbonyloxy, arylcarbonyloxy,        cycloalkylcarbonyloxy, haloalkyloxy, hydroxyalkyloxy,        aralkanoyloxy, aroyloxy, aryloxycarbonylalkyloxy, formyloxy,        Het¹alkyloxy, Het¹oxy, Het¹oxyalkyloxy, Het¹aryloxy,        Het¹aralkyloxy, Het¹cycloalkyloxy, Het¹carbonyloxy,        Het¹oxycarbonyloxy, Het¹alkanoyloxy, Het¹aralkanoyloxy,        Het¹aryloxyalkyloxy, Het¹aroyl, Het²oxy, Het²alkyloxy;        Het²oxyalkyloxy, Het²aralkyloxy, Het²cycloalkyloxy,        Het²alkanoyloxy, Het²aralkanoyloxy, Het²carbonyloxyl,        Het²aryloxy, Het²aryloxyalkyloxy,    -   wherein R¹ R² and R³ are optionally substituted by one or more        substituents independently selected from the group comprising        alkyl, aralkyl, aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl,        carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl,        aminosulfonyl, alkylS(═O)_(t), hydroxy, cyano, halogen or amino        optionally mono- or disubstituted wherein the substituents are        independently selected from the group comprising alkyl, aryl,        aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,        arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,        arylaminoalkoxy, aralkylamino, aryloxyalkylamino,        arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino,        aralkylthio, aryloxyalkylthio, arylaminoalkylthio,        arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl,        Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,        Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio,        Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸,        SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN, CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹),        N₃, NO₂, NR⁸R⁹, N(OH)R⁸, C(O)R⁸, C(S)R⁸, CO₂R⁸, C(O)SR⁸,        C(O)NR⁸R⁹, C(S)NR⁸R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸, NR⁸C(O)R⁹,        NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,        and NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹,        N(OH)C(S)NR⁸R⁹, NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹,        NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, P(O)(OR⁸)(OR⁹),    -   with t being an integer between 1 and 2, and R⁸ R⁹ and R¹⁰ being        each independently selected from the group comprising hydrogen,        hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,        alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino,        arylcarbonylamino, alkylthiocarbonylamino and        arylthiocarbonylamino;    -   and wherein R⁴ is oxo and R⁵ is hydrogen or alkyl.

In particular, the invention relates to a compound having theabove-described formula I, wherein R¹ is formyl (—CHO); wherein R² andR³ are hydroxyl; wherein R⁴ is oxo; and wherein and R⁵ is hydrogen. Thisparticular compound is referred to as 2″ oxo-voruscharin. Thus, thepresent invention provides novel 2″ oxo-voruscharin and Its derivatives.Importantly, these compounds show in vitro as well as in vivo cytotoxicanti-tumor effects and are consequently very suitable for use in allkind of therapeutic applications as described below.

In addition, the present invention relates to pharmaceuticalcompositions comprising the above-described compounds. Furthermore, thepresent Invention relates to the use of said compounds as a medicamentfor the treatment of diseases associated with cell proliferation, inparticular for treatment of cancer. The present invention furtherrelates to the use of the above-described compounds in the preparationof a medicament for the treatment of cancer, and a method of treatingcancer.

DETAILED DESCRIPTION OF THE FIGURES

FIG. 1 represents the anti-tumor activity of the compound uscharin onsix human cancer cell lines.

FIG. 2 to 8 represent the anti-tumor activity of the different compoundsaccording to the invention on six human cancer cell lines. FIG. 2represents the activity of 2″ oxo-voruscharin. FIGS. 3, 4, 5, 6, 7 and 8respectively represent the activity of compounds B, C, D, E, H and I.

FIG. 9 compares the cytotoxic activity of uscharin and 2″oxo-voruscharinon six human cancer cell lines.

FIG. 10 compares the cytotoxic activity of uscharin, 2″oxo-voruscharinand compounds B, C, D, E, H and I on six human cancer cell lines.

FIGS. 11 and 12 represent the effects of the compound uscharin and 2″oxo-voruscharin, respectively on the cell cycle kinetics of Hs683 humancancer cells.

FIGS. 13 and 14 represent the effects of the compound uscharin and 2″oxo-voruscharin, respectively, on the cell cycle kinetics of J82 humancancer cells.

FIGS. 15 and 16 represent the effects of the compound uscharin and 2″oxo-voruscharin, respectively, on the cell cycle kinetics of HCT-15human cancer cells.

FIGS. 17 to 22 represent the anti-tumor effects of compound B ondifferent models of tumor bearing mice. FIG. 17 represents the effect ofcompound B at different concentrations on the tumor size ofMCF-7-TD5-tumor bearing mice. FIG. 18 represents the effect of compoundB on the weight of mice bearing MCF-7-TD5 tumors. FIG. 19 represents theeffect of compound B at different concentrations on the tumor size ofC32-tumor bearing mice. FIG. 20 represents the effect of compound B onthe weight of mice bearing C32 tumors. FIG. 21 represents the death rateof mice bearing A549 tumors after treatment with compound B. FIG. 22represents the effect of compound B on the weight of mice bearing A549tumors.

DETAILED DESCRIPTION

In a first embodiment, the present invention provides for a compound ofthe formula I or a pharmaceutically acceptable salt or ester thereof,

-   -   wherein R¹ is selected from the group comprising hydrogen,        alkyl, alkenyl, alkynyl, alkyloxy, alkyloxyalkyl,        alkylthioalkyl, alkyloxycarbonyl, alkylthiocarbonyl, alkanoyl,        cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl,        cycloalkylthiocarbonyl, cycloalkylalkoxycarbonyl,        cycloalkylalkoxythiocarbonyl, cycloalkylthioalkyl,        alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl,        cycloalkylcarbonyloxyalkyl, silyloxyalkyl, aralkyl, arylalkenyl,        arylcarbonyl, aryloxycarbonyl, arylthiocarbonyl,        aralkoxycarbonyl, arylalkylthiocarbonyl, aryloxyalkyl,        arylthioalkyl, haloalkyl, hydroxyalkyl, aralkanoyl, aroyl,        aryloxycarbonylalkyl, aryloxyalkanoyl, carboxyl, formyl,        alkenylcarbonyl, alkynylcarbonyl, Het¹, Het¹alkyl, Het¹oxyalkyl,        Het¹aryl, Het¹aralkyl, Het¹cycloalkyl, Het¹carbonyl,        Het¹alkoxycarbonyl, Het¹alkylthiocarbonyl, Het¹oxycarbonyl,        Het¹thiocarbonyl, Het¹alkanoyl, Het¹aralkanoyl,        Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,        Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹aroyl,        Het¹oxyalkylcarbonyl, Het¹alkyloxyalkylcarbonyl,        Het¹aryloxyalkylcarbonyl, Het¹carbonyloxyalkyl,        Het¹alkylcarbonyloxyalkyl, Het¹aralkylcarbonyloxyalkyl,        Het²alkyl; Het²oxyalkyl, Het²alkyloxyalkyl, Het²aralkyl,        Het²carbonyl, Het²oxycarbonyl, Het²thiocarbonyl, Het²alkanoyl,        Het¹alkylthiocarbonyl, Het²alkoxycarbonyl, Het²aralkanoyl,        Het²aralkoxycarbonyl, Het²aryloxycarbonyl, Het²aroyl,        Het²aryloxyalkyl, Het²arylthioalkyl, Hat²oxyalkylcarbonyl,        Het²alkyloxyalkylcarbonyl, Het²aryloxyalkylcarbonyl,        Het²carbonyloxyalkyl, Het²alkylcarbonyloxyalkyl,        Het²aralkylcarbonyloxyalkyl, cyano, aminocarbonyl,        aminoalkanoyl, aminoalkyl, CR⁶═NR⁷ or CR⁶═N(OR⁷), with R⁶ and R⁷        being independently selected from the group comprising hydrogen,        hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,        alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino,        arylcarbonylamino, alkylthiocarbonylamino and        arylthiocarbonylamino;    -   wherein R² and R³ are independently selected from the group        comprising hydroxyl, alkyloxy, alkylsilyloxy, arylsilyloxy,        alkyloxyalkyloxy, cycloalkyloxy cycloalkylalkyloxy, aralkyloxy,        aryloxyalkyloxy, silyloxy, alkylcarbonyloxy, arylcarbonyloxy,        cycloalkylcarbonyloxy, haloalkyloxy, hydroxyalkyloxy,        aralkanoyloxy, aroyloxy, aryloxycarbonylalkyloxy, formyloxy,        Het¹alkyloxy, Het¹oxy, Het¹oxyalkyloxy, Het¹aryloxy,        Het¹aralkyloxy, Het¹cycloalkyloxy, Het¹carbonyloxy,        Het¹oxycarbonyloxy, Het¹alkanoyloxy, Het¹aralkanoyloxy,        Het¹aryloxyalkyloxy, Het¹aroyl, Het²oxy, Het²alkyloxy;        Het²oxyalkyloxy, Het²aralkyloxy, Het²cycloalkyloxy,        Het²alkanoyloxy, Het²aralkanoyloxy, Het²carbonyloxyl,        Het²aryloxy, Het²aryloxyalkyloxy,    -   wherein R¹ R² and R³ are optionally substituted by one or more        substituents independently selected from the group comprising        alkyl, aralkyl, aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl,        carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl,        aminosulfonyl, alkylS(═O)_(t), hydroxy, cyano, halogen or amino        optionally mono- or disubstituted wherein the substituents are        independently selected from the group comprising alkyl, aryl,        aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,        arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,        arylaminoalkoxy, aralkylamino, aryloxyalkylamino,        arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino,        aralkylthio, aryloxyalkylthio, arylaminoalkylthio,        arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl,        Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,        Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio,        Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸,        SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN, CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹),        N₃, NO₂, NR⁸R⁹, N(OH)R⁸, C(O)R⁸, C(S)R⁸, CO₂R⁸, C(O)SR⁸,        C(O)NR⁸R⁹, C(S)NR⁸R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸, NR⁸C(O)R⁹,        NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,        and NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹,        N(OH)C(S)NR⁸R⁹, NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹,        NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, P(O)(OR⁸)(OR⁹),    -   with t being an integer between 1 and 2, and R⁸ R⁹ and R¹⁰ being        each independently selected from the group comprising hydrogen,        hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,        alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino,        arylcarbonylamino, alkylthiocarbonylamino and        arylthiocarbonylamino;    -   wherein R⁴ is selected from the group comprising hydrogen, oxo,        is replaced by a double bond between the N atom and the C carbon        atom on the N-containing heterocyclic ring of formula I;        hydroxyl, alkyl, alkenyl, alkynyl, alkanediyl, alkyloxy,        alklylthio, alkylamino, alkyloxyalkyl, arylcarbonylalkyl,        alkylcarbonylalkyl, alkanoyl, cycloalkylcarbonylalkyl,        cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkylamino,        cycloalkylalkyl, cycloalkylalkanoyl, aryl, aralkyl, arylalkenyl,        arylcarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,        aryloxyalkyl, haloalkyloxy, haloalkylthio, haloalkylamino,        hydroxyalkyl, aralkanoyl, aryloxycarbonylalkyl, aryloxyalkanoyl,        Het¹, Het¹alkyl, Het¹oxy, Het¹oxyalkyl, Het¹aryl, Het¹aralkyl,        Het¹cycloalkyl, Het¹aryloxyalkyl, Het¹aroyl, Het², Het²oxy,        Het²alkyl; Het²oxyalkyl, Het²aralkyl, Het²cycloalkyl, Het²aryl,        Het²alkanoyl, Het²aralkanoyl, Het²aroyl, Het²aryloxyalkyl,        aminocarbonyl, aminoalkanoyl, aminoalkyl, optionally substituted        by one or more substituents independently selected from the        group comprising alkyl, aralkyl, aryl, Het¹, Het², cycloalkyl,        alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or        di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,        cyano, halogen or amino optionally mono- or disubstituted        wherein the substituents are independently selected from the        group comprising alkyl, aryl, aralkyl, aryloxy, arylamino,        arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio,        alkoxy, aryloxyalkoxy, aylaminoalkoxy, aralkylamino,        aryloxyalkylamino, arylaminoalkylamino, arylthioalkoxy,        arylthioalkylamino, aralkylthio, aryloxyalkylthio,        arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,        cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino,        Het²amino, Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio,        Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR¹¹, SR¹¹,        SO₂NR¹¹R¹², SO₂N(OH)R¹¹, CN, CR¹¹═NR¹², S(O)R¹¹, SO₂R¹¹,        CR¹¹═N(OR¹²), N₃, NO₂, NR¹¹R¹², N(OH)R¹¹, C(O)R¹¹, C(S)R¹¹,        CO₂R¹¹, C(O)SR¹¹, C(O)NR¹¹R¹², C(S)NR¹¹R¹², C(O)N(OH)R¹²,        C(S)N(OH)R¹¹, NR¹¹C(O)R¹², NR¹¹C(S)R¹², N(OH)C(O)R¹²,        N(OH)C(S)R¹¹, NR¹¹CO₂R¹², NR¹¹C(O)NR¹²R¹³, and NR¹¹C(S)NR¹²R¹³,        N(OH)CO₂R¹¹, NR¹¹C(O)SR¹², N(OH)C(O)NR¹¹R¹², N(OH)C(S)NR¹¹R¹²,        NR¹¹C(O)N(OH)R¹², NR¹¹C(S)N(OH)R¹², NR¹¹SO₂R¹², NHSO₂NR¹¹R¹²,        NR¹¹SO₂NHR¹², P(O)(OR¹¹)(OR¹²), wherein t is an integer between        1 and 2, R¹¹, R¹² and R¹³ are each independently selected from        the group comprising hydrogen, alkyl, alkenyl, and alkynyl; and    -   wherein R⁵ is selected from the group comprising hydrogen, oxo,        hydroxyl, alkyl, alkenyl, alkynyl, alkanediyl, alkyloxy,        alkyloxyalkyl, arylcarbonylalkyl, alkylcarbonylalkyl, alkanoyl,        cycloalkylcarbonylalkyl, cycloalkyl, cycloalkylalkyl,        cycloalkylalkanoyl, aryl, aralkyl, arylalkenyl, arylcarbonyloxy,        aryloxycarbonyloxy, aralkoxycarbonyloxy, aryloxyalkyl,        haloalkyl, hydroxyalkyl, aralkanoyl, aryloxycarbonylalkyl,        aryloxyalkanoyl, Het¹, Het¹alkyl, Het¹oxy, Het¹oxyalkyl,        Het¹aryl, Het¹aralkyl, Het¹cycloalkyl, Het¹aryloxyalkyl,        Het¹aroyl, Het², Het²oxy, Het²alkyl; Het²oxyalkyl, Het²aralkyl,        Het²cycloalkyl, Het²aryl, Het²alkanoyl, Het²aralkanoyl,        Het²aroyl, Het²aryloxyalkyl, aminocarbonyl, aminoalkanoyl,        aminoalkyl, optionally substituted by one or more substituents        independently selected from the group comprising alkyl, aralkyl,        aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,        aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,        alkylS(═O)_(t), hydroxy, cyano, halogen or amino optionally        mono- or disubstituted wherein the substituents are        independently selected from the group comprising alkyl, aryl,        aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,        arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,        aylaminoalkoxy, aralkylamino, aryloxyalkylamino,        arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino,        aralkylthio, aryloxyalkylthio, arylaminoalkylthio,        arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl,        Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,        Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio,        Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR¹¹, SR¹¹,        SO₂NR¹¹R¹², SO₂N(OH)R¹¹, CN, CR¹¹═NR¹², S(O)R¹¹, SO₂R¹¹,        CR¹¹═N(OR¹²), N₃, NO₂, NR¹¹R¹², N(OH)R¹¹, C(O)R¹¹, C(S)R¹¹,        CO₂R¹¹, C(O)SR¹¹, C(O)NR¹¹R¹², C(S)NR¹¹R¹², C(O)N(OH)R¹²,        C(S)N(OH)R¹¹, NR¹¹C(O)R¹², NR¹¹C(S)R¹², N(OH)C(O)R¹²,        N(OH)C(S)R¹¹, NR¹¹CO₂R¹², NR¹¹C(O)NR¹²R¹³, and NR¹¹C(S)NR¹²R¹³,        N(OH)CO₂R¹¹, NR¹¹C(O)SR¹², N(OH)C(O)NR¹¹R¹², N(OH)C(S)NR¹¹R¹²,        NR¹¹C(O)N(OH)R¹², NR¹¹C(S)N(OH)R¹², NR¹¹SO₂R¹², NHSO₂NR¹¹R¹²,        NR¹¹SO₂NHR¹², P(O)(OR¹¹)(OR¹²), wherein t is an integer between        1 and 2, R¹¹, R¹² and R¹³ are each independently selected from        the group comprising hydrogen, alkyl, alkenyl, and alkynyl.

In another embodiment, the present invention relates to a compound ofthe formula I, wherein R¹ is selected from the group comprising alkyl,alkenyl, alkynyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl,alkyloxycarbonyl, alkylthiocarbonyl, alkanoyl, cycloalkylalkyl,cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylthiocarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkoxythiocarbonyl,cycloalkylthioalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl,cycloalkylcarbonyloxyalkyl, silyloxyalkyl, aralkyl, arylalkenyl,arylcarbonyl, aryloxycarbonyl, arylthiocarbonyl, aralkoxycarbonyl,arylalkylthiocarbonyl, aryloxyalkyl, arylthioalkyl, haloalkyl,hydroxyalkyl, aralkanoyl, aroyl, aryloxycarbonylalkyl, aryloxyalkanoyl,carboxyl, formyl, alkenylcarbonyl, alkynylcarbonyl, Het¹, Het¹alkyl,Het¹oxyalkyl, Het¹aryl, Het¹aralkyl, Het¹cycloalkyl, Het¹carbonyl,Het¹alkoxycarbonyl, Het¹alkylthiocarbonyl, Het¹oxycarbonyl,Het¹thiocarbonyl, Het¹alkanoyl, Het¹aralkanoyl, Het¹aryloxyalkyl,Het¹alkyloxyalkyl, Het¹arylthioalkyl, Het¹aryloxycarbonyl,Het¹aralkoxycarbonyl, Het¹aroyl, Het¹oxyalkylcarbonyl,Het¹alkyloxyalkylcarbonyl, Het¹aryloxyalkylcarbonyl,Het¹carbonyloxyalkyl, Het¹alkylcarbonyloxyalkyl,Het¹aralkylcarbonyloxyalkyl, Het²alkyl; Het²oxyalkyl, Het²alkyloxyalkyl,Het²aralkyl, Het²carbonyl, Het²oxycarbonyl, Het²thiocarbonyl,Het²alkanoyl, Het²alkylthiocarbonyl, Het²alkoxycarbonyl, Het²aralkanoyl,Het²aralkoxycarbonyl, Het²aryloxycarbonyl, Het²aroyl, Het²aryloxyalkyl,Het²arylthioalkyl, Het²oxyalkylcarbonyl, Het²alkyloxyalkylcarbonyl,Het²aryloxyalkylcarbonyl, Het²carbonyloxyalkyl,Het²alkylcarbonyloxyalkyl, Het²aralkylcarbonyloxyalkyl, cyano,aminocarbonyl, aminoalkanoyl, aminoalkyl, CR⁶═NR⁷ or CR⁶═N(OR⁷)

-   -   with R⁶ and R⁷ being independently selected from the group        comprising hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,        Het¹aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl,        alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino        and arylthiocarbonylamino;    -   wherein R² and R³ are independently selected from the group        comprising hydroxyl, alkyloxy, alkylsilyloxy, arylsilyloxy,        alkyloxyalkyloxy, cycloalkyloxy cycloalkylalkyloxy, aralkyloxy,        aryloxyalkyloxy, silyloxy, alkylcarbonyloxy, arylcarbonyloxy,        cycloalkylcarbonyloxy, haloalkyloxy, hydroxyalkyloxy,        aralkanoyloxy, aroyloxy, aryloxycarbonylalkyloxy, formyloxy,        Het¹alkyloxy, Het¹oxy, Het¹oxyalkyloxy, Het¹aryloxy,        Het¹aralkyloxy, Het¹cycloalkyloxy, Het¹carbonyloxy,        Het¹oxycarbonyloxy, Het¹alkanoyloxy, Het¹aralkanoyloxy,        Het¹aryloxyalkyloxy, Het¹aroyl, Het²oxy, Het²alkyloxy;        Het²oxyalkyloxy, Het²aralkyloxy, Het²cycloalkyloxy,        Het²alkanoyloxy, Het²aralkanoyloxy, Het²carbonyloxyl,        Het²aryloxy, Het²aryloxyalkyloxy,    -   wherein R¹ R² and R³ are optionally substituted by one or more        substituents independently selected from the group comprising        alkyl, aralkyl, aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl,        carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl,        aminosulfonyl, alkylS(═O)_(t), hydroxy, cyano, halogen or amino        optionally mono- or disubstituted wherein the substituents are        independently selected from the group comprising alkyl, aryl,        aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,        arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,        arylaminoalkoxy, aralkylamino, aryloxyalkylamino,        arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino,        aralkylthio, aryloxyalkylthio, arylaminoalkylthio,        arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl,        Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,        Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio,        Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸,        SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN, CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹),        N₃, NO₂, NR⁸R⁹, N(OH)R⁸, C(O)R⁸, C(S)R⁸, CO₂R⁸, C(O)SR⁸,        C(O)NR⁸R⁹, C(S)NR⁸R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸, NR⁸C(O)R⁹,        NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,        and NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹,        N(OH)C(S)NR⁸R⁹, NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹,        NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, P(O)(OR⁸)(OR⁹),    -   with t being an integer between 1 and 2, and R⁸ R⁹ and R¹⁰ being        each independently selected from the group comprising hydrogen,        hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,        alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino,        arylcarbonylamino, alkylthiocarbonylamino and        arylthiocarbonylamino;    -   and wherein R⁴ is oxo and R⁶ is hydrogen or alkyl.

Whenever the term “substituted” is used in the present invention, it ismeant to indicate that one or more hydrogens on the atom indicated inthe expression using “substituted” is replaced with a selection from theindicated group, provided that the indicated atom's normal valency isnot exceeded, and that the substitution results in a chemically stablecompound, i.e. a compound that is sufficiently robust to surviveisolation to a useful degree of purity from a reaction mixture, andformulation into a therapeutic agent.

As used herein, the term “halo” or “halogen” as a group or part of agroup is generic for fluoro, chloro, bromo or iodo.

The term “alkyl”, alone or in combination, means straight and branchedchained saturated hydrocarbon radicals containing from 1 to 10 carbonatoms, preferably from 1 to 8 carbon atoms, more preferably 1 to 6carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 2-methylbutyl,pentyl, iso-amyl, hexyl, 3-methylpentyl, octyl and the like.

The term “alkenyl”, alone or in combination, defines straight andbranched chained hydrocarbon radicals containing from 2 to about 18carbon atoms, preferably from 2 to 8 carbon atoms, more preferably 2-6carbon atoms containing at least one double bond such as, for example,ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.

The term “alkynyl”, alone or in combination, defines straight andbranched chained hydrocarbon radicals having from 2 to 10 carbon atomscontaining at least one triple bond, more preferably from 2 to about 6carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl,(propargyl), butynyl, pentynyl, hexynyl and the like.

The term “cycloalkyl” alone or in combination, means a saturated orpartially saturated monocyclic, bicyclic or polycyclic alkyl radicalwherein each cyclic moiety contains from about 3 to about 8 carbonatoms, more preferably from about 3 to about 7 carbon atoms. Examples ofmonocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examplesof polycyclic cycloalkyl radicals include decahydronaphthyl, bicyclo[5.4.0] undecyl, adamantyl, and the like.

The term “cycloalkylalkyl” means an alkyl radical as defined herein, inwhich at least one hydrogen atom on the alkyl radical is replaced by acycloalkyl radical as defined herein. Examples of such cycloalkylalkylradicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl,2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl,cyclopentylpropyl, 3-cyclopentylbutyl, cyclohexylbutyl and the like.

The term “aryl” alone or in combination, is meant to include phenyl andnaphtyl which both may be optionally substituted with one or moresubstituents independently selected from alkyl, alkoxy, halogen,hydroxy, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl,cycloalkyl, Het¹, amido, optionally mono- or disubstitutedaminocarbonyl, methylthio, methylsulfonyl, and phenyl optionallysubstituted with one or more substituents selected from C₁₋₆alkyl,C₁₋₆alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino,nitro, cyano, haloC₁₋₆alkyl, carboxyl, C₁₋₆alkoxycarbonyl,C₃₋₇cycloalkyl, Het¹, optionally mono- or disubstituted aminocarbonyl,methylthio and methylsulfonyl; whereby the optional substituents on anyamino function are independently selected from alkyl, alkyloxy, Het¹,Het¹alkyl, Het¹alkyl, Het¹oxy, Het¹oxyalkyl, phenyl, phenyloxy,phenyloxyalkyl, phenylalkyl, alkyloxycarbonylamino, amino, andaminoalkyl whereby each of the amino groups may optionally be mono- orwhere possible di-substituted with alkyl. Examples of aryl includesphenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl,3-methyl-4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl,3-aminophenyl, 3-acetamidophenyl, 4-acetamidophenyl,2-methyl-3-acetamidophenyl, 2-methyl-3-aminophenyl,3-methyl-4-aminophenyl, 2-amino-3-methylphenyl,2,4dimethyl-3-aminophenyl, 4-hydroxyphenyl, 3-methyl-4hydroxyphenyl,1-naphthyl, 2-naphthyl, 3-amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl,6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl and the like.

The term “aralkyl” alone or in combination, means an alkyl as definedherein, wherein an alkyl hydrogen atom is replaced by an aryl as definedherein. Examples of aralkyl radicals include benzyl, phenethyl,dibenzylmethyl, methylphenylmethyl, 3-(2-naphthyl)-butyl, and the like.

As used herein, the term “oxo” or “═O” forms a carbonyl moiety with thecarbon atom to which it is attached. The term “formyl” or “—CHO” is analdehyde moiety whereby the C atom binds to the carbon atom to which itis attached. As used herein, the term “formyloxy” or “—OCHO” forms aformic ester moiety whereby the oxygen atom binds to the carbon atom towhich it is attached. As used herein, the term “carboxyl” or “—COOH” isan acid moiety whereby the carbon atom binds to the carbon atom to whichit is attached.

The term “haloalkyl” alone or in combination, means an alkyl radicalhaving the meaning as defined above wherein one or more hydrogens arereplaced with a halogen, preferably, chloro or fluoro atoms, morepreferably fluoro atoms. Examples of such haloalkyl radicals includechloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1,1,1-trifluoroethyl and the like.

The term “Het¹” alone or in combination, is defined as a saturated orpartially unsaturated monocyclic, bicyclic or polycyclic heterocyclehaving preferably 3 to 12 ring members, more preferably 5 to 10 ringmembers and more preferably 5 to 6 ring members, which contains one ormore heteroatom ring members selected from nitrogen, oxygen or sulfurand which is optionally substituted on one or more carbon atoms byalkyl, alkyloxy, halogen, hydroxy, oxo, optionally mono- ordisubstituted amino, nitro, cyano, haloalkyl, carboxyl, alkoxycarbonyl,cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio,methylsulfonyl, aryl and a saturated or partially unsaturatedmonocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ringmembers which contains one or more heteroatom ring members selected fromnitrogen, oxygen or sulfur and whereby the optional substituents on anyamino function are independently selected from alkyl, alkyloxy, Het²,Het²alkyl, Het²oxy, Het²oxyalkyl, aryl, aryloxy, aryloxyalkyl, aralkyl,alkyloxycarbonylamino, amino, and aminoalkyl whereby each of the aminogroups may optionally be mono- or where possible di-substituted withalkyl.

The term “Het²” as a group or part of a group is defined as an aromaticmonocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 12ring members, more preferably 5 to 10 ring members and more preferably 5to 6 ring members, which contains one or more heteroatom ring membersselected from nitrogen, oxygen or sulfur and which is optionallysubstituted on one or more carbon atoms by alkyl, alkyloxy, halogen,hydroxy, optionally mono- or disubstituted amino, nitro, cyano,haloalkyl, carboxyl, alkoxycarbonyl, cycloalkyl, optionally mono- ordisubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het¹ andan aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 12ring members; whereby the optional substituents on any amino functionare independently selected from alkyl, alkyloxy, Het¹, Het¹alkyl,Het¹oxy, Het¹oxyalkyl, aryl, aryloxy, aryloxyalkyl, aralkyl,alkyloxycarbonylamino, amino, and aminoalkyl whereby each of the aminogroups may optionally be mono- or where possible di-substituted withalkyl.

The term “alkoxy” or “alkyloxy”, alone or in combination, means an alkylether radical wherein the term alkyl is as defined above. Examples ofsuitable alkyl ether radicals include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, hexanoxy andthe like.

The term “arylthioalkoxy” means alkoxy as defined herein, wherein analkyl hydrogen atom is replaced by an arylthio as defined herein.Examples of (arylthio) alkoxy radicals include 2-(phenylthio)-ethoxy,and the like.

The term “alkanoyl” or “alkylcarbonyl”, alone or in combination, meansan acyl radical derived from an alkanecarboxylic acid, examples of whichinclude acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and thelike.

The term “alkylamino” means an alkyl amine radical, wherein the term“alkyl” is defined as above. Examples of alkylamino radicals includemethylamino (NHCH₃), ethylamino (NHCH₂CH₃), n-propylamino,isopropylamino, n-butylamino, isobutylamino, sec-butylamino,tert-butylamino, n-hexylamino, and the like.

The term “alkylthio” means an alkyl thioether radical, wherein the term“alkyl” is defined as above. Examples of alkylthio radicals includemethylthio (SCH₃), ethylthio (SCH₂CH₃), n-propylthio, isopropylthio,n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-hexylthio,and the like.

The term “aminoalkanoyl” means an acyl group derived from anamino-substituted alkylcarboxylic acid wherein the amino group can be aprimary, secondary or tertiary amino group containing substituentsselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like.

The term “aminocarbonyl” alone or in combination, means anamino-substituted carbonyl (carbamoyl) group wherein the amino group canbe a primary, secondary or tertiary amino group containing substituentsselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like.

The term “aralkanoyl” means an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as phenylacetyl,3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl,and the like.

The term “aralkoxy” means alkoxy as defined herein, wherein an alkylhydrogen atom is replaced by an aryl as defined herein. Examples ofaralkoxy radicals include 2-phenylethoxy, 2-phenyl-1-propoxy, and thelike.

The term “aralkoxycarbonyl”, alone or in combination, means a radical ofthe formula aralkyl-O—C(O)— in which the term “aralkyl” has thesignificance given above. Examples of an aralkoxycarbonyl radical arebenzyloxycarbonyl and 4-methoxyphenylmethoxycarbonyl.

The term “aralkylamino” means alkylamino as defined herein, wherein analkyl hydrogen atom is replaced by an aryl as defined herein. Examplesof aralkylamino radicals include 2-phenethylamino,4-phenyl-n-butylamino, and the like.

The term “aralkylthio” means alkylthio as defined herein, wherein analkyl hydrogen atom is replaced by an aryl as defined herein. Examplesof aralkylthio radicals include 3-phenyl-2-propylthio,2-(2-naphthyl)-ethylthio, and the like.

The term “aroyl” means an acyl radical derived from an arylcarboxylicacid, aryl having the meaning given above. Examples of sucharylcarboxylic acid radicals include substituted and unsubstitutedbenzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl,4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl,2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl,3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl,3-(benzyloxyformamidol-2-naphthoyl, and the like.

The term “arylaminoalkoxy” means alkoxy as defined herein, wherein analkyl hydrogen atom is replaced by an arylamino as defined herein.Examples of (arylamino)alkoxy radicals include 2-(phenylamino)-ethoxy,2-(2-naphthylamino)-1-butoxy, and the like.

The term “arylaminoalkyl” means alkyl as defined herein, wherein analkyl hydrogen atom is replaced by an arylamino as defined herein.Examples of arylaminoalkyl radicals include phenylaminoethyl,4-(3-methoxyphenylamino)-1-butyl, and the like.

The term “arylaminoalkylamino” means alkylamino as defined herein,wherein an alkyl hydrogen atom is replaced by an arylamino as definedherein. Examples of (arylamino)alkylamino radicals include3-(naphthylamino)-propylamino, 4-(phenylamino)-1-butylamino, and thelike.

The term “arylaminoalkylthio” means alkylthio as defined herein, whereinan alkyl hydrogen atom is replaced by an arylamino as defined herein.Examples of (arylamino)alkylthio radicals include2-(phenylamino)-ethylthio, 3-(2-naphthylamino)-n-propylthio, and thelike.

The term “aryloxy” means a radical of the formula aryl-O— in which theterm aryl has the significance given above.

The term “aryloxyalkanoyl” means an acyl radical of the formulaaryl-O-alkanoyl wherein aryl and alkanoyl have the meaning given above.

The term “aryloxyalkoxy” means alkoxy as defined herein, wherein analkyl hydrogen atom is replaced by an aryloxy as defined herein.Examples of (aryloxy)alkoxy radicals include 2-phenoxyethoxy,4-(3-aminophenoxy)-1-butoxy, and the like.

The term “aryloxyalkyl” means alkyl as defined herein, wherein an alkylhydrogen atom is replaced by an aryloxy as defined herein. Examples ofaryloxyalkyl radicals include phenoxyethyl, 4-(3-aminophenoxy-butyl, andthe like.

The term “aryloxyalkylamino” means alkylamino as defined herein, whereinan alkyl hydrogen atom is replaced by an aryloxy as defined herein.Examples of (aryloxy)alkylamino radicals include 3-phenoxy-npropylamino,4-phenoxybutylamino, and the like.

The term “aryloxyalkylthio” means alkylthio as defined herein, whereinan alkyl hydrogen atom is replaced by an aryloxy as defined herein.Examples of (aryloxy)alkylthio radicals include 3-phenoxypropylthio, 4(2-fluorophenoxy)-butylthio, and the like.

The term “arylthioalkylamino” means alkylamino as defined herein,wherein an alkyl hydrogen atom is replaced by an arylthio as definedherein. Examples of (arylthio)alkylamino radicals include2-(phenylthio)-ethylamino, and the like.

The term “arylthioalkylthio” means alkylthio as defined herein, whereinan alkyl hydrogen atom is replaced by an arylthio as defined herein.Examples of (arylthio)alkylthio radicals include2-(naphthylthio)-ethylthio, 3-(phenylthio)-propylthio, and the like.

The term “cycloalkylalkoxycarbonyl” means an acyl group derived from acycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O—COOHwherein cycloalkylalkyl has the meaning given above.

The term “cycloalkylcarbonyl” means an acyl group derived from amonocyclic or bridged cycloalkanecarboxylic acid such ascyclopropylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, and thelike, or from a benz-fused monocyclic cycloalkanecarboxylic acid whichis optionally substituted by one or more substituents selected fromalkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl,carboxy, alkoxycarbonyl, cycloalkyl, heterocycloalkyl, alkanoylamino,amido, mono and dialkyl substituted amino, mono and dialkyl substitutedamido and the like, such as 1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.

The term “Het²alkoxy” means alkoxy as defined herein, wherein an alkylhydrogen atom is replaced by a Het² as defined herein. Examples ofHet²alkoxy radicals include 2-pyridylmethoxy, 4-(I-imidazolyl)-butoxy,and the like.

The term “Het²alkyl” means alkyl as defined herein, wherein an alkylhydrogen atom is replaced by a Het as defined herein. Examples ofHet²alkyl radicals include 2-pyridylmethyl, 3-(4-thiazolyl)-propyl, andthe like.

The term “Het²alkylamino” means alkylamino as defined herein, wherein analkyl hydrogen atom is replaced by a Het² as defined herein. Examples ofHet²alkylamino radicals include 4-pyridylmethylamino, 3(2-furanyl)-propylamino, and the like.

The term “Het²alkylthio” means alkylthio as defined herein, wherein analkyl hydrogen atom is replaced by a Het² as defined herein. Examples ofHet²alkylthio radicals include 3-pyridylmethylthio, 3(4-thiazolyl)-propylthio, and the like.

The term “Het²amino” means Het² as defined herein, wherein a hydrogenatom on the Het² ring is replaced by a nitrogen. Het²amino radicalsinclude, for example, 4-thiazolylamino, 2-pyridylamino, and the like.

The term “Het²oxy” means Het² as defined herein, wherein a hydrogen atomon the Het² ring is replaced by an oxygen. Het²oxy radicals include, forexample, 4-pyridyloxy, 5-quinolyloxy, and the like.

The term “Het²oxycarbonyl” means an acyl radical derived from a carbonicacid represented by Het²-O—COOH wherein Het² has the meaning givenabove.

The term “Het²thio” means Het² as defined herein, wherein a hydrogenatom on the Het² ring is replaced by a sulfur. Het²thio radicalsinclude, for example, 3-pyridylthio, 3-quinolylthio, 4-imidazolylthio,and the like.

The term “Het¹alkanoyl” is an acyl radical derived from aHet¹-substituted alkylcarboxylic acid wherein Het¹ has the meaning givenabove.

The term “Het¹alkoxycarbonyl” means an acyl group derived fromHet¹-O—COOH wherein Het¹ is as defined above.

As used herein before, the term “one or more” covers the possibility ofall the available C-atoms, where appropriate, to be substituted,preferably, one, two or three. When any variable, e.g. halogen or alkyl,occurs more than one time in any constituent, each definition isindependent.

According to another embodiment, the present invention relates to acompound having the formula I, wherein R¹ is selected from the groupcomprising hydrogen, alkyl, hydroxyalkyl, alkenyl, alkynyl,alkyloxyalkyl, alkylthioalkyl, alkyloxycarbonyl, alkanoyl,cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl,cycloalkylalkoxycarbonyl, cycloalkylthioalkyl, alkylcarbonyloxyalkyl,arylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl, silyloxyalkyl,aralkyl, arylalkenyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl,arylthioalkyl, aralkanoyl, aroyl, carboxyl, formyl, alkenylcarbonyl,alkynylcarbonyl, Het¹oxyalkyl, Het¹alkoxycarbonyl, Het¹oxycarbonyl,Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹oxyalkylcarbonyl,Het¹alkyloxyalkylcarbonyl, Het¹aryloxyalkylcarbonyl,Het¹carbonyloxyalkyl, Het¹alkylcarbonyloxyalkyl,Het¹aralkylcarbonyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²oxycarbonyl, Het²alkoxycarbonyl, Het²aralkoxycarbonyl,Het²aryloxycarbonyl, Het²aryloxyalkyl, Het²arylthioalkyl,Het²oxyalkylcarbonyl, Het²alkyloxyalkylcarbonyl,Het²aryloxyalkylcarbonyl, Het²carbonyloxyalkyl,Het²alkylcarbonyloxyalkyl, Het²aralkylcarbonyloxyalkyl, CR⁶═NR⁷,CR⁶═N(OR⁷),

-   -   with R⁶ and R⁷ being independently selected from the group        comprising hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,        Het¹aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl,        alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino        and arylthiocarbonylamino;    -   wherein R² and R³ are independently selected from the group        comprising hydroxyl, alkyloxy, alkyloxyalkyloxy, cycloalkyloxy        cycloalkylalkyloxy, aralkyloxy, aryloxyalkyloxy, silyloxy,        alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy,        aryloxycarbonylalkyloxy, formyloxy, Het¹alkyloxy, Het¹oxy,        Het¹oxyalkyloxy, Het¹aryloxy, Het¹aralkyloxy, Het¹cycloalkyloxy,        Het¹carbonyloxy, Het¹alkanoyloxy, Het¹aralkanoyloxy,        Het¹aryloxyalkyloxy, Het²oxy, Het²alkyloxy; Het²oxyalkyloxy,        Het²aralkyloxy, Het²cycloalkyloxy, Het²alkanoyloxy,        Het²aralkanoyloxy, Het²carbonyloxyl, Het²aryloxy,        Het²aryloxyalkyloxy,    -   wherein R¹ R² and R³ are optionally substituted by one or more        substituents independently selected from the group indicated in        claim 1; and    -   wherein R⁴ is selected from the group comprising, oxo,        hydroxyalkyl, alkyl, alkenyl, alkylcarbonylalkyl,        arylcarbonylalkyl and R⁵ is hydrogen, oxo, hydroxyl,        hydroxyalkyl, alkyl, alkenyl, alkylcarbonylalkyl,        arylcarbonylalkyl.

According to a further embodiment, the present invention relates to acompound having the formula I, wherein R¹ is selected from the groupcomprising alkyl, alkenyl, alkynyl, alkyloxyalkyl, alkylthioalkyl,alkyloxycarbonyl, alkanoyl, cycloalkylalkyl, cycloalkylcarbonyl,cycloalkylalkanoyl, cycloalkylalkoxycarbonyl, cycloalkylthioalkyl,alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl,silyloxyalkyl, aralkyl, arylalkenyl, arylcarbonyl, aryloxycarbonyl,aralkoxycarbonyl, arylthioalkyl, aralkanoyl, aroyl, carboxyl, formyl,alkenylcarbonyl, alkynylcarbonyl, Het¹oxyalkyl, Het¹alkoxycarbonyl,Het¹oxycarbonyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹oxyalkylcarbonyl,Het¹alkyloxyalkylcarbonyl, Het¹aryloxyalkylcarbonyl,Het¹carbonyloxyalkyl, Het¹alkylcarbonyloxyalkyl,Het¹aralkylcarbonyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²oxycarbonyl, Het²alkoxycarbonyl, Het²aralkoxycarbonyl,Het²aryloxycarbonyl, Het²aryloxyalkyl, Het²arylthioalkyl,Het²oxyalkylcarbonyl, Het²alkyloxyalkylcarbonyl,Het²aryloxyalkylcarbonyl, Het²carbonyloxyalkyl,Het²alkylcarbonyloxyalkyl, Het²aralkylcarbonyloxyalkyl, CR⁶═NR⁷,CR⁶═N(OR⁷),

-   -   with R⁶ and R⁷ being independently selected from the group        comprising hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,        Het¹aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl,        alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino        and arylthiocarbonylamino;    -   wherein R² and R³ are independently selected from the group        comprising hydroxyl, alkyloxy, alkyloxyalkyloxy, cycloalkyloxy        cycloalkylalkyloxy, aralkyloxy, aryloxyalkyloxy, silyloxy,        alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy,        aryloxycarbonylalkyloxy, formyloxy, Het¹alkyloxy, Het¹oxy,        Het¹oxyalkyloxy, Het¹aryloxy, Het¹aralkyloxy, Het¹cycloalkyloxy,        Het¹carbonyloxy, Het¹alkanoyloxy, Het¹aralkanoyloxy,        Het¹aryloxyalkyloxy, Het²oxy, Het²alkyloxy; Het²oxyalkyloxy,        Het²aralkyloxy, Het²cycloalkyloxy, Het²alkanoyloxy,        Het²aralkanoyloxy, Het²carbonyloxyl, Het²aryloxy,        Het²aryloxyalkyloxy,    -   wherein R¹ R² and R³ are optionally substituted by one or more        substituents independently selected from the group indicated        above; and    -   wherein R⁴ is oxo and R⁵ is hydrogen or alkyl.

According to a preferred embodiment, the present invention relates to acompound having the formula I, wherein R¹ is selected from the groupcomprising alkyl, alkenyl, alkynyl, alkyloxyalkyl, alkylthioalkyl,alkanoyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl,cycloalkylthioalkyl, silyloxyalkyl, aralkyl, arylalkenyl, arylcarbonyl,arylthioalkyl, aralkanoyl, aroyl, carboxyl, formyl, alkenylcarbonyl,alkynylcarbonyl, Het¹oxyalkyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl,Het¹arylthioalkyl, Het¹oxyalkylcarbonyl, Het¹alkyloxyalkylcarbonyl,Het¹aryloxyalkylcarbonyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²aryloxyalkyl, Het²arylthioalkyl, Het²oxyalkylcarbonyl,Het²alkyloxyalkylcarbonyl, Het²aryloxyalkylcarbonyl, CR⁶═NR⁷,CR⁶═N(OR⁷),

-   -   with R⁶ and R⁷ being independently selected from the group        comprising hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,        Het¹aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl,        alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino        and arylthiocarbonylamino;    -   wherein R² and R³ are independently selected from the group        comprising hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,        cycloalkylcarbonyloxy, formyloxy, Het¹carbonyloxy,        Het¹alkanoyloxy, Het¹aralkanoyloxy, Het²carbonyloxyl,        Het²alkanoyloxy, Het²aralkanoyloxy,    -   wherein R¹ R² and R³ are optionally substituted by one or more        substituents independently selected from the group indicated        above; and    -   wherein R⁴ is oxo and R⁵ is hydrogen or alkyl.

According to yet another preferred embodiment, the present inventionrelates to a compound having the formula I wherein R¹ is selected fromthe group comprising alkyl, alkenyl, alkynyl, alkyloxyalkyl,alkylthioalkyl, cycloalkylalkyl, cycloalkylthioalkyl, silyloxyalkyl,aralkyl, arylalkenyl, arylthioalkyl, carboxyl, formyl, Het¹oxyalkyl,Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl, Het²oxyalkyl,Het²alkyloxyalkyl, Het²aryloxyalkyl, Het²arylthioalkyl, optionallysubstituted by one or more substituents independently selected from thegroup indicated above; wherein R² and R³ are hydroxyl and wherein R⁴ isoxo and R⁵ is hydrogen.

According to an even more preferred embodiment, the present inventionrelates to a compound having the formula I wherein R¹ is selected fromthe group comprising alkyl, alkenyl, alkynyl, alkyloxyalkyl,cycloalkylalkyl, silyloxyalkyl, aralkyl, arylalkenyl, carboxyl, formyl,Het¹oxyalkyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het²oxyalkyl,Het²alkyloxyalkyl, Het²aryloxyalkyl, optionally substituted by one ormore substituents independently selected from the group indicated above;an wherein R² and R³ are hydroxyl, R⁴ is oxo and R⁵ is hydrogen.

Even more preferred, the compound according to any the invention has anR¹ being selected from the group comprising alkyl, carboxyl, formyl; anR² and R³ group being hydroxyl, an R⁴ group being oxo and a R⁵ beinghydrogen.

In a preferred embodiment, the present invention relates to a compoundhaving formula I, wherein R¹ is formyl, R² and R³ are hydroxyl R⁴ is oxoand R⁵ is hydrogen. This particular compound is referred to herein as 2″oxo-voruscharin and is represented by the formula II:

According to another embodiment, the present invention relates to acompound having the formula I, wherein R¹ is selected from the groupcomprising hydrogen, alkyl, alkenyl, alkynyl, alkyloxyalkyl,hydroxyalkyl, alkylthioalkyl, alkanoyl, cycloalkylalkyl,cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylthioalkyl,silyloxyalkyl, aralkyl, arylalkenyl, arylcarbonyl, arylthioalkyl,aralkanoyl, aroyl, carboxyl, formyl, alkenylcarbonyl, alkynylcarbonyl,Het¹oxyalkyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,Het¹oxyalkylcarbonyl, Het¹alkyloxyalkylcarbonyl,Het¹aryloxyalkylcarbonyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²aryloxyalkyl, Het²arylthioalkyl, Het²oxyalkylcarbonyl,Het²alkyloxyalkylcarbonyl, Het²aryloxyalkylcarbonyl, CR⁶═NR⁷,CR⁶═N(OR⁷),

-   -   with R⁶ and R⁷ being independently selected from the group        comprising hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,        Het¹aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl,        alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino        and arylthiocarbonylamino;    -   wherein R² and R³ are independently selected from the group        comprising hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,        cycloalkylcarbonyloxy, formyloxy, Het¹carbonyloxy,        Het¹alkanoyloxy, Het¹aralkanoyloxy, Het²carbonyloxyl,        Het²alkanoyloxy, Het²aralkanoyloxy,    -   wherein R¹ R² and R³ are optionally substituted by one or more        substituents independently selected from the group indicated in        claim 1; and    -   wherein R⁴ is oxo, hydroxyalkyl, alkyl, alkenyl,        arylcarbonylaryl, alkylcarbonylalkyl and R⁵ is hydrogen or        alkyl.

In yet another preferred embodiment, the present invention relates to acompound of formula I, wherein R¹ is selected from the group comprisinghydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkyloxyalkyl,alkylthioalkyl, cycloalkylalkyl, cycloalkylthioalkyl, silyloxyalkyl,aralkyl, arylalkenyl, arylthioalkyl, carboxyl, formyl, Het¹oxyalkyl,Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl, Het²oxyalkyl,Het²alkyloxyalkyl, Het²aryloxyalkyl, Het²arylthioalkyl, optionallysubstituted by one or more substituents independently selected from thegroup indicated in claim 1; wherein R² and R³ are hydroxyl and whereinR⁴ is hydroxyalkyl, arylcarbonylalkyl, alkylcarbonylalkyl and R⁵ ishydrogen.

In a more preferred embodiment, the compound of the formula I has R¹which is selected from the group comprising hydrogen, alkyl, alkenyl,alkynyl, hydroxyalkyl, alkyloxyalkyl, cycloalkylalkyl, silyloxyalkyl,aralkyl, arylalkenyl, carboxyl, formyl, Het¹oxyalkyl, Het¹aryloxyalkyl,Het¹alkyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl, Het²aryloxyalkyl,optionally substituted by one or more substituents independentlyselected from the group indicated in claim 1; wherein R² and R³ arehydroxyl, R⁴ is hydroxyalkyl, arylcarbonylalkyl, alkylcarbonylalkyl andR⁵ is hydrogen.

In particular, the present invention relates to compounds of the formulaI wherein R¹ is selected from the group comprising alkyl, hydroxyalkyl,carboxyl, formyl; wherein R² and R³ are hydroxyl, and wherein R⁴ isarylcarbonylalkyl and R⁵ is hydrogen. More in particular, the presentinvention relates to compounds of the formula 1 wherein R¹ ishydroxyalkyl, R² and R³ are hydroxyl, R⁴ is arylcarbonylalkyl and R⁵ ishydrogen.

The present invention aims to provide novel cardenolide glycosides,which have a cytotoxic activity, and which can consequently be used forin medical applications.

As explained above, the present invention provides novel 2″oxo-voruscharin and its derivatives. In another aspect, the presentinvention also relate to novel derivatives of the C. procera cardenolideglycoside uscharin. The novel uscharin derivatives according to theinvention may be either extracted from the plant or synthesized.

In another embodiment the present invention thus relates to a compoundof the formula Ia or a pharmaceutically acceptable salt thereof,

-   -   wherein R¹ is selected from the group comprising alkyl, alkenyl,        alkynyl, alkyloxyalkyl, alkylthioalkyl, alkyloxycarbonyl,        alkanoyl, cycloalkylalkyl, cycloalkylcarbonyl,        cycloalkylalkanoyl, cycloalkylalkoxycarbonyl,        cycloalkylthioalkyl, alkylcarbonyloxyalkyl,        arylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl, silyloxyalkyl,        aralkyl, arylalkenyl, arylcarbonyl, aryloxycarbonyl,        aralkoxycarbonyl, arylthioalkyl, aralkanoyl, aroyl,        silyloxyalkyl, carboxyl, alkenylcarbonyl, alkynylcarbonyl,        Het¹oxyalkyl, Het¹alkoxycarbonyl, Het¹oxycarbonyl,        Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,        Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹oxyalkylcarbonyl,        Het¹alkyloxyalkylcarbonyl, Het¹aryloxyalkylcarbonyl,        Het¹carbonyloxyalkyl, Het¹alkylcarbonyloxyalkyl,        Het¹aralkylcarbonyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl,        Het²oxycarbonyl, Het²alkoxycarbonyl, Het²aralkoxycarbonyl,        Het²aryloxycarbonyl, Het²aryloxyalkyl, Het²arylthioalkyl,        Het²oxyalkylcarbonyl, Het²alkyloxyalkylcarbonyl,        Het²aryloxyalkylcarbonyl, Het²carbonyloxyalkyl,        Het²alkylcarbonyloxyalkyl, Het²aralkylcarbonyloxyalkyl, CR⁶═NR⁷,        CR⁶═N(OR⁷),    -   with R⁶ and R⁷ being independently selected from the group        comprising hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,        Het¹aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl,        alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino        and arylthiocarbonylamino;    -   wherein R² and R³ have the same definition as indicated above;    -   wherein R¹ R² and R³ are optionally substituted by one or more        substituents independently selected from the group as indicated        above, and    -   wherein R⁴ and R⁵ are hydrogen or alkyl.

In a preferred embodiment the uscharin derivative according to theinvention is a compound having the formula Ia, wherein R¹ is selectedfrom the group comprising alkyl, alkenyl, alkynyl, alkyloxyalkyl,alkylthioalkyl, alkanoyl, cycloalkylalkyl, cycloalkylcarbonyl,cycloalkylalkanoyl, cycloalkylthioalkyl, silyloxyalkyl, aralkyl,arylalkenyl, arylcarbonyl, arylthioalkyl, aralkanoyl, aroyl,silyloxyalkyl, carboxyl, alkenylcarbonyl, alkynylcarbonyl, Het¹oxyalkyl,Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,Het¹oxyalkylcarbonyl, Het¹alkyloxyalkylcarbonyl,Het¹aryloxyalkylcarbonyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²aryloxyalkyl, Het²arylthioalkyl, Het²oxyalkylcarbonyl,Het²alkyloxyalkylcarbonyl, Het²aryloxyalkylcarbonyl, CR⁶═NR⁷,CR⁶═N(OR⁷), with R⁶ and R⁷ being independently selected from the groupcomprising hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl,alkenyl, alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino,arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino;wherein R² and R³ have the same definition as above indicated; whereinR¹ R² and R³ are optionally substituted by one or more substituentsindependently selected from the group as indicated above, and wherein R⁴and R⁵ are hydrogen or alkyl.

In a even more preferred embodiment, the invention relates to anuscharin derivative having the formula Ia, wherein R¹ is selected fromthe group comprising alkyl, alkenyl, alkynyl, alkyloxyalkyl,alkylthioalkyl, cycloalkylalkyl, cycloalkylthioalkyl, silyloxyalkyl,aralkyl, arylalkenyl, arylthioalkyl, silyloxyalkyl, carboxyl,Het¹oxyalkyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,Het²oxyalkyl, Het²alkyloxyalkyl, Het²aryloxyalkyl, Het²arylthioalkyl,optionally substituted by one or more substituents independentlyselected from the group indicated in above; wherein R² and R³ arehydroxyl and wherein R⁴ and R⁵ are hydrogen or alkyl.

In another preferred embodiment, the invention relates to an uscharinderivative having the formula Ia, wherein R¹ is selected from the groupcomprising alkyl, alkenyl, alkynyl, alkyloxyalkyl, cycloalkylalkyl,silyloxyalkyl, aralkyl, arylalkenyl, carboxyl, Het¹oxyalkyl,Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²aryloxyalkyl, optionally substituted by one or more substituentsindependently selected from the group indicated above; wherein R² and R³are hydroxyl and wherein R⁴ and R⁵are hydrogen.

Another further embodiment of the invention relates to a compound offormula Ib,

wherein R¹ is selected from the group comprising alkenyl, alkynyl,alkyloxyalkyl, alkylthioalkyl, alkyloxycarbonyl, alkanoyl,cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl,cycloalkylalkoxycarbonyl, cycloalkylthioalkyl, alkylcarbonyloxyalkyl,arylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl, silyloxyalkyl,aralkyl, arylalkenyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl,arylthioalkyl, aralkanoyl, aroyl, silyloxyalkyl, carboxyl,alkenylcarbonyl, alkynylcarbonyl, Het¹oxyalkyl, Het¹alkoxycarbonyl,Het¹oxycarbonyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹oxyalkylcarbonyl,Het¹alkyloxyalkylcarbonyl, Het¹aryloxyalkylcarbonyl,Het¹carbonyloxyalkyl, Het¹alkylcarbonyloxyalkyl,Het¹aralkylcarbonyloxyalkyl, Het¹oxyalkyl, Het²alkyloxyalkyl,Het²oxycarbonyl, Het²alkoxycarbonyl, Het²aralkoxycarbonyl,Het²aryloxycarbonyl, Het²aryloxyalkyl, Het²arylthioalkyl,Het²oxyalkylcarbonyl, Het²alkyloxyalkylcarbonyl,Het²aryloxyalkylcarbonyl, Het²carbonyloxyalkyl,Het²alkylcarbonyloxyalkyl, Het²aralkylcarbonyloxyalkyl, CR⁶═NR⁷,CR⁶═N(OR⁷),

-   -   with R⁶ and R⁷ being independently selected from the group        comprising hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,        Het¹aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl,        alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino        and arylthiocarbonylamino;    -   wherein R¹ is optionally substituted by one or more substituents        independently selected from the group as indicated above,    -   wherein R² and R³ are hydroxyl and wherein R⁴ is replaced by a        double bond between the N atom and the C carbon atom of the        N-containing heterocyclic ring of formula I; and wherein R⁵ is        hydrogen.

According to this embodiment, this compound may also be represented bythe formula III:

In a further embodiment, the present invention relates to a compound offormula III, wherein R¹ is selected from the group comprising alkenyl,alkynyl, alkyloxyalkyl, cycloalkylalkyl, silyloxyalkyl, aralkyl,arylalkenyl, carboxyl, Het¹oxyalkyl, Het¹aryloxyalkyl,Het¹alkyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl, Het²aryloxyalkyl,optionally substituted by one or more substituents independentlyselected from the group indicated in above.

Non-limiting examples of compounds according to the present inventioninclude compound of the formula I wherein R¹ is formyl, R² and R³ arehydroxyl, R⁴ is oxo and R⁵ is hydrogen; compound of the formula Iwherein R¹ is hydroxymethylene, R² and R³ are hydroxyl, R⁴ isphenylcarbonylmethylene and R⁵ is hydrogen, compound of the formula Iwith R¹ being hydroxymethylene, R² and R³ are hydroxyl, R⁴ is oxo and R⁵is hydrogen, compound of the formula I with R¹ being acetyloxymethylene,R² and R³ are hydroxyl, R⁴ is oxo and R⁵ is hydrogen; compound of theformula I wherein R¹ is benzoyloxymethylene, R² and R³ are hydroxyl, R⁴is oxo and R⁵ is hydrogen; compound of the formula I, wherein R¹ ishydroxymethylene, R² and R³ are hydroxyl, R⁴ is replaced by a doublebond between the N atom and the C carbon atom of the N-containingheterocyclic ring of formula I; and R⁵ is hydrogen; compound of theformula I wherein R¹ is acetyloxymethylene, R² and R³ are hydroxyl, R⁴is replaced by a double bond between the N atom and the C carbon atom ofthe N-containing heterocyclic ring of formula I; and R⁵ is hydrogen;compound of the formula I wherein R¹ is benzoyloxymethylene, R² and R³are hydroxyl, R⁴ is replaced by a double bond between the N atom and theC carbon atom of the N-containing heterocyclic ring of formula I; and R⁵is hydrogen.

Whenever used hereinafter, the term “Compounds of the invention” or“derivatives” or “analogues” or a similar term is meant to include thecompounds of general formula I, formula II or formula III, i.e. the 2″oxo-voruscharin and its derivatives, the uscharin derivatives and anysubgroup thereof. This term also refers to the compounds as depicted inTable A and their N-oxides, salts, stereoisomeric forms, racemicmixtures, pro-drugs, esters and metabolites, as well as theirquaternized nitrogen derivatives. The N-oxide forms of said compoundsare meant to comprise compounds wherein one or several nitrogen atomsare oxidized to the so-called N-oxide.

The term “pro-drug” as used herein means the pharmacologicallyacceptable derivatives such as esters, amides and phosphates, such thatthe resulting in vivo biotransformation product of the derivative is theactive drug. The reference by Goodman and Gilman (The PharmacologicalBasis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992,“Biotransformation of Drugs”, p 13-15) describing pro-drugs generally ishereby incorporated. Pro-drugs of the compounds of the invention can beprepared by modifying functional groups present in said component insuch a way that the modifications are cleaved, either in routinemanipulation or in vivo, to the parent component. Typical examples ofpro-drugs are described for instance in WO 99/33795, WO 99/33815, WO99/33793 and WO 99/33792 all incorporated herein by reference. Pro-drugsare characterized by excellent aqueous solubility, increasedbioavailability and are readily metabolized into the active inhibitorsin vivo.

The compounds according to the invention may also exist in theirtautomeric forms. Such forms, although not explicitly indicated in thecompounds described herein, are intended to be included within the scopeof the present invention.

The term stereochemically isomeric forms of the compounds according tothe invention, as used herein, defines all possible compounds made up ofthe same atoms bonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of the present invention may possess. Unless otherwisementioned or indicated, the chemical designation of a compound hereinencompasses the mixture of all possible stereochemically isomeric forms,which said compound may possess. Said mixture may contain alldiastereomers and/or enantiomers of the basic molecular structure ofsaid compound. All stereochemically isomeric forms of the compounds ofthe invention either in pure form or in admixture with each other areintended to be embraced within the scope of the present invention.

For therapeutic use, the salts of the compounds according to theinvention are those wherein the counterion is pharmaceutically orphysiologically acceptable.

The pharmaceutically acceptable salts of the compounds according to theinvention, i.e. in the form of water-, oil-soluble, or dispersibleproducts, include the conventional non-toxic salts or the quaternaryammonium salts which are formed, e.g., from inorganic or organic acidsor bases. Examples of such acid addition salts include acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.Base salts include ammonium salts, alkali metal salts such as sodium andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth. Also, the basic nitrogen-containinggroups may be quaternized with such agents as lower alkyl halides, suchas methyl, ethyl, propyl, and butyl chloride, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl-bromides and others. Other pharmaceutically acceptable saltsinclude the sulfate salt ethanolate and sulfate salts.

The pharmaceutically acceptable esters of the compounds according to theinvention refer to non-toxic esters, preferably the alkyl esters such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters, ofwhich the methyl ester is preferred. However, other esters such asphenyl-alkyl may be employed if desired.

The compounds according to the invention show cytotoxic activities,which implies that the may be used in various medical applications. Asis demonstrated in the examples given below, the compounds according tothe invention have in vitro anti-tumor activity.

Furthermore, the compounds according to the invenbon exhibit a lowtoxicity level. “Toxicity” is related to the detrimental effect acompound may exhibit on healthy cells, tissues or organs. The toxicitylevel of the compounds according to the invention is surprisingly low.The compounds according to the invention combine the essential featuresof a good anti-tumor activity and a low level of toxicity. Consequentlythe compounds according to the invention may be used in pharmaceuticalcompositions for the treatment of various diseases. In addition, becausethey have a low level of toxicity the compounds according to theinvention may be used during longer periods of treatments.

The present invention also relates to a pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and a therapeuticamount of a compound according to the invention. More in particular, thepresent invention relates to a pharmaceutical composition comprising atherapeutically effective amount of 2″ oxo-voruscharin and apharmaceutically acceptable excipient.

The term “therapeutically effective amount” as used herein means thatamount of active compound or component or pharmaceutical agent thatelicits the biological or medicinal response in a tissue, system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease being treated.

The pharmaceutical composition can be prepared in a manner known per seto one of skill in the art. For this purpose, at least one compoundaccording to the invention having formula I or any subgroup orderivative thereof, one or more solid or liquid pharmaceuticalexcipients and, if desired, in combination with other pharmaceuticalactive compounds, are brought into a suitable administration form ordosage form which can then be used as a pharmaceutical in human medicineor veterinary medicine.

Particular forms of the pharmaceutical composition may be, for example,solutions, suspensions, emulsions, creams, tablets, capsules, nasalsprays, liposomes or micro-reservoirs, especially compositions in orallyingestible or sterile injectable form, for example, as sterileinjectable aqueous or oleaginous suspensions or suppositories. Thepreferred form of composition contemplated is the dry solid form, whichincludes capsules, granules, tablets, pills, boluses and powders. Thesolid carrier may comprise one or more excipients, e.g. lactose,fillers, disintegrating agents, binders, e.g. cellulose,carboxymethylcellulose or starch or anti-stick agents, e.g. magnesiumstearate, to prevent tablets from adhering to tabletting equipment.Tablets, pills and boluses may be formed so as to disintegrate rapidlyor to provide slow release of the active ingredient.

In order to enhance the solubility and/or the stability of the compoundsof a pharmaceutical composition according to the invention, it can beadvantageous to employ α-, β- or γ-cyclodextrins or their derivatives.In addition, co-solvents such as alcohols may improve the solubilityand/or the stability of the compounds. In the preparation of aqueouscompositions, addition of salts of the compounds of the invention areobviously more suitable due to their increased water solubility.

Appropriate cyclodextrins are α-, β- or γ-cyclodextrins (CDs) or ethersand mixed ethers thereof wherein one or more of the hydroxy groups ofthe anhydroglucose units of the cyclodextrin are substituted with alkyl,particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD;hydroxyalkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl;carboxyalkyl, particularly carboxymethyl or carboxyethyl; alkylcarbonyl,particularly acetyl; alkyloxycarbonylalkyl or carboxyalkyloxyalkyl,particularly carboxymethoxypropyl or carboxyethoxypropyl;alkylcarbonyloxyalkyl, particularly 2-acetyloxypropyl. Especiallynoteworthy as complexants and/or solubilizers are β-CD, randomlymethylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD). The term mixed ether denotes cyclodextrin derivativeswherein at least two cyclodextrin hydroxy groups are etherified withdifferent groups such as, for example, hydroxypropyl and hydroxyethyl.An interesting way of formulating the compounds according to theinvention in combination with a cyclodextrin or a derivative thereof hasbeen described in EP-A-721,331. Although the formulations describedtherein are with antifungal active ingredients, they are equallyinteresting for formulating the compounds according to the invention.Said formulations may also be rendered more palatable by addingpharmaceutically acceptable sweeteners and/or flavors.

More in particular, the compositions may be formulated in apharmaceutical formulation comprising a therapeutically effective amountof particles consisting of a solid dispersion of the compounds of theinvention and one or more pharmaceutically acceptable water-solublepolymers.

The term “a solid dispersion” defines a system in a solid state (asopposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed more or less evenlythroughout the other component or components. When said dispersion ofthe components is such that the system is chemically and physicallyuniform or homogenous throughout or consists of one phase as defined inthermodynamics, such a solid dispersion is referred to as “a solidsolution”. Solid solutions are preferred physical systems because thecomponents therein are usually readily bioavailable to the organisms towhich they are administered. The term “a solid dispersion” alsocomprises dispersions that are less homogenous throughout than solidsolutions. Such dispersions are not chemically and physically uniformthroughout or comprise more than one phase.

The water-soluble polymer is conveniently a polymer that has-an apparentviscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution at20° C. solution. Preferred water-soluble polymers are hydroxypropylmethylcelluloses or HPMC. HPMC having a methoxy degree of substitutionfrom about 0.8 to about 2.5 and a hydroxypropyl molar substitution fromabout 0.05 to about 3.0 are generally water soluble. Methoxy degree ofsubstitution refers to the average number of methyl ether groups presentper anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molarsubstitution refers to the average number of moles of propylene oxidewhich have reacted with each anhydroglucose unit of the cellulosemolecule. The compounds according to the invention as definedhereinabove can be prepared by first preparing a solid dispersion of thecompounds according to the invention, and then optionally grinding ormilling that dispersion. Various techniques exist for preparing soliddispersions including melt-extrusion, spray-drying andsolution-evaporation, melt-extrusion being preferred.

It may further be convenient to formulate the compounds according to theinvention in the form of nanoparticles which have a surface modifieradsorbed on the surface thereof in an amount sufficient to maintain aneffective average particle size of less than 1000 nm. Suitable surfacemodifiers can preferably be selected from known organic and inorganicpharmaceutical excipients. Such excipients include various polymers, lowmolecular weight oligomers, natural products and surfactants. Preferredsurface modifiers include nonionic and anionic surfactants.

Yet another interesting way of formulating the compounds according tothe invention involves a pharmaceutical composition whereby thecompounds are incorporated in hydrophilic polymers and applying thismixture as a coat film over many small beads, thus yielding acomposition with good bio-availability which can conveniently bemanufactured and which is suitable for preparing pharmaceutical dosageforms for oral administration. Said beads comprise (a) a central,rounded or spherical core, (b) a coating film of a hydrophilic polymerand an antiretroviral agent and (c) a seal-coating polymer layer.Materials suitable for use as cores in the beads are manifold, providedthat said materials are pharmaceutically acceptable and have appropriatedimensions and firmness. Examples of such materials are polymers,inorganic substances, organic substances, and saccharides andderivatives thereof.

Another important feature attributed to the compounds according to theinvention is their broad application possibility. The compoundsaccording to the invention are highly active against several types ofcancers. As will be shown in the examples described below, the compoundsaccording to the invention exert significant anti-tumor effects onseveral tumor models tested, including glioma, colon, lung and bladdercancer (see examples). Importantly, the compounds according to theinvention exhibit anti-tumor activity on a broad panel of histologicaltumor types.

Therefore, due to their favorable pharmacological properties thecompounds according to the present invention are particularly suitablefor use as medicaments in the treatment of individuals suffering fromdiseases associated with cell proliferation. In another embodiment, thecompounds according to the present invention are used as a medicament.In yet another embodiment, the compounds according to the presentinvention are used in the preparation of a medicament for treatingdiseases associated with cell proliferation. In particular the compoundsaccording to the present invention are used in the preparation of amedicament for treating cancer.

The term “individual,” as used herein refers to an animal, preferably amammal, and most preferably a human, who has been the object oftreatment, observation or experiment.

The term “diseases associated with cell proliferation” as used hereinrefers to, but is not limited to, any type of cancer or conditioninvolving cell proliferation. The compounds of the invention may beespecially used in the treatment of cancers such as, but not limited to,leukemia, non-small cell lung cancer, small cell lung cancer, coloncancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostatecancer, breast cancer, glioma, bladder cancer, head and neck cancer,pancreas cancer, skin cancer, liver cancer, bone cancer and lymphoma.

In addition, the compounds according to the invention may also be verysuitable in the treatment of scar tissue and wounds. It is believed thatmost, if not all, of the compounds of the present invention can act asactive ingredients in treating scar tissue and in promoting woundhealing and tissue regeneration.

In another embodiment, the invention relates to a method of treatment ofdiseases associated with cell proliferation comprising administrating toan individual in need of such treatment a pharmaceutical compositionaccording to the invention. In particular, the invention relates to amethod of treating cancer comprising administrating to an individual inneed of such treatment a pharmaceutical composition according to theinvention.

For these purposes, the pharmaceutical composition of the presentinvention may be administered orally, parenterally, i.e. includingsubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques, by inhalation spray, or rectally, indosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles.

In accordance with the method of the present invention, saidpharmaceutical composition can be administered separately at differenttimes during the course of therapy or concurrently in divided or singlecombination forms. The present invention is therefore to be understoodas embracing all such regimes of simultaneous or alternating treatmentand the term “administering” is to be interpreted accordingly.

Essentially, the primary modes of treatment of solid tumor cancerscomprise surgery, radiation therapy and chemotherapy, separately and incombination. The compounds according to the invention are suitable foruse in combination with these medicinal techniques. The compounds of theinvention may be useful in increasing the sensitivity of tumor cells toradiation in radiotherapy and also in potentiating or enhancing damageto tumors by chemotherapeutic agents. The compounds and theirpharmaceutically acceptable salts may also be useful for sensitizingmultidrug-resistant tumor cells. The compounds according to theinvention are useful therapeutic compounds for administration inconjunction with other DNA-damaging cytotoxic drugs or radiation used inradiotherapy to potentiate their effect.

In another embodiment of the method of the invention, the administrationmay be performed with food, e.g., a high-fat meal. The term ‘with food’means the consumption of a meal either during or no more than about onehour before or after administration of a pharmaceutical compositionaccording to the invention.

For an oral administration form, the compositions of the presentinvention can be mixed with suitable additives, such as excipients,stabilizers or inert diluents, and brought by means of the customarymethods into the suitable administration forms, such as tablets, coatedtablets, hard capsules, aqueous, alcoholic, or oily solutions. Examplesof suitable inert carriers are gum arabic, magnesia, magnesiumcarbonate, potassium phosphate, lactose, glucose, or starch, inparticular, corn starch. In this case, the preparation can be carriedout both as dry and as moist granules. Suitable oily excipients orsolvents are vegetable or animal oils, such as sunflower oil or codliver oil. Suitable solvents for aqueous or alcoholic solutions arewater, ethanol, sugar solutions, or mixtures thereof. Polyethyleneglycols and polypropylene glycols are also useful as further auxiliariesfor other administration forms. As immediate release tablets, thesecompositions may contain microcrystalline cellulose, dicalciumphosphate, starch, magnesium stearate and lactose and/or otherexcipients, binders, extenders, disintegrants, diluents and lubricantsknown in the art.

The oral administration of a pharmaceutical composition comprising acompound according to the invention, or a pharmaceutically acceptablesalt or ester thereof, is suitably accomplished by uniformly andintimately blending together a suitable amount of a compound accordingto the invention in the form of a powder, optionally also including afinely divided solid carrier, and encapsulating the blend in, forexample, a hard gelatin capsule. The solid carrier can include one ormore substances, which act as binders, lubricants, disintegratingagents, coloring agents, and the like. Suitable solid carriers include,for example, calcium phosphate, magnesium stearate, talc, sugars,lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, lowmelting waxes and ion exchange resins.

Oral administration of a pharmaceutical composition comprising acompound according to the invention, or a pharmaceutically acceptablesalt or ester thereof can also be accomplished by preparing capsules ortablets containing the desired amount of a compound according to theinvention, optionally blended with a solid carrier as described above.Compressed tablets containing the pharmaceutical composition of theinvention can be prepared by uniformly and intimately mixing the activeingredient with a solid carrier such as described above to provide amixture having the necessary compression properties, and then compactingthe mixture in a suitable machine to the shape and size desired. Moldedtablets maybe made by molding in a suitable machine, a mixture ofpowdered compound according to the invention moistened with an inertliquid diluent.

When administered by nasal aerosol or inhalation, these compositions maybe prepared according to techniques well-known in the art ofpharmaceutical formulation and may be prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or othersolubilizing or dispersing agents known in the art. Suitablepharmaceutical formulations for administration in the form of aerosolsor sprays are, for example, solutions, suspensions or emulsions of thecompounds of the invention or their physiologically tolerable salts in apharmaceutically acceptable solvent, such as ethanol or water, or amixture of such solvents. If required, the formulation can alsoadditionally contain other pharmaceutical auxiliaries such assurfactants, emulsifiers and stabilizers as well as a propellant.

For subcutaneous or intravenous administration, the active compounds ofthe invention, if desired with the substances customary therefor such assolubilizers, emulsifiers or further auxiliaries, are brought intosolution, suspension, or emulsion. The compounds of the invention canalso be lyophilized and the lyophilizates obtained used, for example,for the production of injection or infusion preparations. Suitablesolvents are, for example, water, physiological saline solution oralcohols, e.g. ethanol, propanol, glycerol, in addition also sugarsolutions such as glucose or mannitol solutions, or alternativelymixtures of the various solvents mentioned. The injectable solutions orsuspensions may be formulated according to known art, using suitablenon-toxic, parenterally-acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodiumchloride solution, or suitable dispersing or wetting and suspendingagents, such as sterile, bland, fixed oils, including synthetic mono- ordiglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, theseformulations may be prepared by mixing the compounds according to theinvention with a suitable non-irritating excipient, such as cocoabutter, synthetic glyceride esters or polyethylene glycols, which aresolid at ordinary temperatures, but liquidify and/or dissolve in therectal cavity to release the drug.

The pharmaceutical compositions of this invention can be administered tohumans in dosage ranges specific for each compound of the inventioncomprised in said compositions. The compounds comprised in saidcomposition can be administered together or separately.

It will be understood, however, that specific dose level and frequencyof dosage for any particular patient may be varied and will depend upona variety of factors including the activity of the specific compound ofthe invention employed, the metabolic stability and length of action ofthat compound, the age, body weight, general health, sex, diet, mode andtime of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

The compounds according to the invention may be prepared by a method ofchemical synthesis, starting from 2″oxo-voruscharin or uscharin or othercompounds. The methods of synthesis of the compounds according to theinvention involve chemical modifications of 2″oxo-voruscharin oruscharin or derivatives thereof. 2″oxo-voruscharin or uscharin can beobtained by any convenient method, for example by chemical synthesis.Alternatively, it may also be obtained from extraction and purificationfrom e.g. plants of the Asclepiadacaeae family, which produce2″oxo-voruscharin and uscharin naturally, e.g. Calotropis procera.

The following examples are meant to illustrate the present invention.These examples are presented to exemplify the invention and are not tobe considered as limiting the scope of the invention.

EXAMPLES

Example 1 provides a non-limiting list of examples of compoundsaccording to the invention. Example 2 illustrates the preparation ofcertain compounds according to the invention. Example 3 and 4 illustratethe in vitro anti-tumor effects of several compounds according to theinvention. The anti-tumor effects of the compounds according to theinvention are compared to the anti-tumor activity of uscharin. Example 5relates to the determination of the Maximum Tolerated Dose for thecompounds according to the invention. Example 6 relates to thedetermination of the in-vivo anti-tumor pharmacology of the compoundsaccording to the invention, in different cancer models.

Example 1 Non-limiting Examples of Compounds According to the Inventionare Listed Hereunder in Table A

R¹ R² R³ R⁴ R⁵ —COOH —OH —OH ═O —H —CO₂CH₃ —OH —OH ═O —H —CO₂C₂H₅ —OH—OH ═O —H —CHO —OH —OH ═O —H —CH₂OH —OH —OH ═O —H —CHOHCH₃ —OH —OH ═O —H—CH₂—CH₂—CH═CH₂ —OH —OH ═O —H —COOCH₃ —OH —OH ═O —H —CH₂OCH₃ —OH —OH ═O—H —CH₂OCH₂CH₃ —OH —OH ═O —H —CH₂SCH₃ —OH —OH ═O —H —CH═N—OH —OH —OH ═O—H

—OH —OH ═O —H

—OH —OH ═O —H

—OH —OH ═O —H

—OH —OH ═O —H

—OH —OH ═O —H

—OH —OH ═O —H

—OH —OH ═O —H

—OH —OH ═O —H

—OH —OH ═O —H

—OH —OH ═O —H

—OH —OH ═O —H

—OH —OH ═O —H

—OH —OH ═O —H —COOH —O—CH₂CH₃ —O—CH₃ —H ═O —CO₂CH₃ —O—CH₂CH₃ —O—CH₃ —H═O —CO₂C₂H₅ —O—CH₂CH₃ —O—CH₃ —H ═O —CHO —O—CH₂CH₃ —O—CH₃ —H ═O —CH₂OH—O—CH₂CH₃ —O—CH₃ —H ═O —CHOHCH₃ —O—CH₂CH₃ —O—CH₃ —H ═O —CH₂—CH₂—CH═CH₂—O—CH₂CH₃ —O—CH₃ —H ═O —COOCH₃ —O—CH₂CH₃ —O—CH₃ ═O —H —CH₂OCH₃ —O—CH₂CH₃—O—CH₃ ═O —H —CH₂OCH₂CH₃ —O—CH₂CH₃ —O—CH₃ ═O —H —CH₂SCH₃ —O—CH₂CH₃—O—CH₃ ═O —H —CH═N—OH —O—CH₂CH₃ —O—CH₃ ═O —H

—O—CH₂CH₃ —O—CH₃ ═O —H

—O—CH₂CH₃ —O—CH₃ ═O —H

—O—CH₂CH₃ —O—CH₃ ═O —H

—O—CH₂CH₃ —O—CH₃ ═O —H

—O—CH₂CH₃ —O—CH₃ ═O —H

—O—CH₂CH₃ —O—CH₃ ═O —H

—O—CH₂CH₃ —O—CH₃ ═O —H

—O—CH₂CH₃ —O—CH₃ ═O —H

—O—CH₂CH₃ —O—CH₃ ═O —H

—O—CH₂CH₃ —O—CH₃ ═O —H

—O—CH₂CH₃ —O—CH₃ ═O —H

—O—CH₂CH₃ —O—CH₃ ═O —H

—O—CH₂CH₃ —O—CH₃ ═O —H —COOH —OH —OCOH ═O —H —CO₂CH₃ —OH —OCOH ═O —H—CO₂C₂H₅ —OH —OCOH ═O —H —CH₂OH —OH —OCOH ═O —H —CHOHCH₃ —OH —OCOH ═O —H—CH₂—CH₂—CH═CH₂ —OH —OCOH ═O —H

—OH —OCOH ═O —H

—OH —OCOH ═O —H

—OH —OCOH ═O —H

—OH —OCOH ═O —H

—OH —OCOH ═O —H

—OH —OCOH ═O —H

—OH —OCOH ═O —H

—OH —OCOH ═O —H

—OH —OCOH ═O —H

—OH —OCOH ═O —H

—OH —OCOH ═O —H

—OH —OCOH ═O —H

—OH —OCOH ═O —H —COOH —OH —OH —H —H —CO₂CH₃ —OH —OH —H —H —CO₂C₂H₅ —OH—OH —H —H —OH —OH —OH —H —H —CH₂OH —OH —OCOH —H —H —CHOHCH₃ —OH —OCOH —H—H —CH₂—CH₂—CH═CH₂ —OH —OCOH —H —H

—OH —OCOH H —H

—OH —OH —H —H

—OH —OH —H —H

—OH —OH —H —H

—OH —OH —H —H

—OH —OCOH —H —H

—OH —OCOH —H —H

—OH —OCOH —H —H

—OH —OCOH H —H

—OH —OH —H —H

—OH —OH —H —H

—OH —OH —H —H

—OH —OH —H —H —COOH —OCH₃ —OCH₃ ═O —CH₂CH₃ —CO₂CH₃ —OCH₃ —OCH₃ ═O—CH₂CH₃ —CO₂C₂H₅ —OCH₃ —OCH₃ ═O —CH₂CH₃ —CHO —OCH₃ —OCH₃ ═O —CH₂CH₃—CH₂OH —OCH₃ —OCH₃ ═O —CH₂CH₃ —CHOHCH₃ —OCH₃ —OCH₃ ═O —CH₂CH₃—CH₂—CH₂—CH═CH₂ —OCH₃ —OCH₃ ═O —CH₂CH₃ —COOCH₃ —OCH₃ —OCH₃ ═O —CH₂CH₃—CH₂OCH₃ —OCH₃ —OCH₃ ═O —CH₂CH₃ —CH₂OCH₂CH₃ —OCH₃ —OCH₃ ═O —CH₂CH₃—CH₂SCH₃ —OCH₃ —OCH₃ ═O —CH₂CH₃ —CH═N—OH —OCH₃ —OCH₃ ═O —CH₂CH₃

—OCH₃ —OCH₃ ═O —CH₂CH₃

—OCH₃ —OCH₃ ═O —CH₂CH₃

—OCH₃ —OCH₃ ═O —CH₂CH₃

—OCH₃ —OCH₃ ═O —CH₂CH₃

—OCH₃ —OCH₃ ═O —CH₂CH₃

—OCH₃ —OCH₃ ═O —CH₂CH₃

—OCH₃ —OCH₃ ═O —CH₂CH₃

—OCH₃ —OCH₃ ═O —CH₂CH₃

—OCH₃ —OCH₃ ═O —CH₂CH₃

—OCH₃ —OCH₃ ═O —CH₂CH₃

—OCH₃ —OCH₃ ═O —CH₂CH₃

—OCH₃ —OCH₃ ═O —CH₂CH₃

—OCH₃ —OCH₃ ═O —CH₂CH₃ —COOH

—OCH₂CH₃ —H —CH₂CH₃ —CO₂CH₃

—OCH₂CH₃ —H —CH₂CH₃ —CO₂C₂H₅

—OCH₂CH₃ —H —CH₂CH₃ —CHO

—OCH₂CH₃ —H —CH₂CH₃ —CH₂OH

—OCH₂CH₃ —H —CH₂CH₃ —CHOHCH₃

—OCH₂CH₃ —H —CH₂CH₃ —CH₂—CH₂—CH═CH₂

—OCH₂CH₃ —H —CH₂CH₃ —COOCH₃

—OCH₂CH₃ —H —CH₂CH₃ —CH₂OCH₃

—OCH₂CH₃ —H —CH₂CH₃ —CH₂OCH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃ —CH₂SCH₃

—OCH₂CH₃ —H —CH₂CH₃ —CH═N—OH

—OCH₂CH₃ —H —CH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃

—OCH₂CH₃ —H —CH₂CH₃ —COOH —O—CH₂CH₃

—CH₂CH₃ —H —CO₂CH₃ —O—CH₂CH₃

—CH₂CH₃ —H —CO₂C₂H₅ —O—CH₂CH₃

—CH₂CH₃ —H —CHO —O—CH₂CH₃

—CH₂CH₃ —H —CH₂OH —O—CH₂—CH₃

—CH₂CH₃ —H —CHOHCH₃ —O—CH₂CH₃

—CH₂CH₃ —H —CH₂—CH₂—CH═CH₂ —O—CH₂CH₃

—CH₂CH₃ —H —COOCH₃ —O—CH₂CH₃

—CH₂CH₃ —H —CH₂OCH₃ —O—CH₂CH₃

—CH₂CH₃ —H —CH₂OCH₂CH₃ —O—CH₂CH₃

—CH₂CH₃ —H —CH₂SCH₃ —O—CH₂CH₃

—CH₂CH₃ —H —CH═N—OH —O—CH₂CH₃

—CH₂CH₃ —H

—O—CH₂CH₃

—CH₂CH₃ —H

—O—CH₂CH₃

—CH₂CH₃ —H

—O—CH₂CH₃

—CH₂CH₃ —H

—O—CH₂CH₃

—CH₂CH₃ —H

—O—CH₂CH₃

—CH₂CH₃ —H

—O—CH₂CH₃

—CH₂CH₃ —H

—O—CH₂CH₃

—CH₂CH₃ —H

—O—CH₂CH₃

—CH₂CH₃ —H

—O—CH₂CH₃

—CH₂CH₃ —H

—O—CH₂CH₃

—CH₂CH₃ —H

—O—CH₂CH₃

—CH₂CH₃ —H

—O—CH₂CH₃

—CH₂CH₃ —H

—O—CH₂CH₃

—CH₂CH₃ —H —COOH

—O—CH₃ —CH₂CH₃ —CH₂CH₃ —CO₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃ —CO₂C₂H₅

—O—CH₃ —CH₂CH₃ —CH₂CH₃ —CHO

—O—CH₃ —CH₂CH₃ —CH₂CH₃ —CH₂OH

—O—CH₃ —CH₂CH₃ —CH₂CH₃ —CHOHCH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃ —CH₂—CH₂CH═CH₂

—O—CH₃ —CH₂CH₃ —CH₂CH₃ —COOCH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃ —CH₂OCH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃ —CH₂OCH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃ —CH₂SCH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃ —CH═N—OH

—O—CH₃ —CH₂CH₃ —CH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃

—O—CH₃ —CH₂CH₃ —CH₂CH₃ —COOH —OH —OH Double bond* —H —CO₂CH₃ —OH —OHDouble bond* —H —CO₂C₂H₅ —OH —OH Double bond* —H —CH₂OH —OH —OH Doublebond* —H —CHOHCH₃ —OH —OH Double bond* —H —CH₂—CH₂—CH═CH₂ —OH —OH Doublebond* —H —COOCH₃ —OH —OH Double bond* —H —CH₂OCH₃ —OH —OH Double bond*—H —CH₂OCH₂CH₃ —OH —OH Double bond* —H —CH₂SCH₃ —OH —OH Double bond* —H—CH═N—OH —OH —OH Double bond* —H

—OH —OH Double bond* —H

—OH —OH Double bond* —H

—OH —OH Double bond* —H

—OH —OH Double bond* —H

—OH —OH Double bond* —H

—OH —OH Double bond* —H

—OH —OH Double bond* —H

—OH —OH Double bond* —H

—OH —OH Double bond* —H

—OH —OH Double bond* —H

—OH —OH Double bond* —H

—OH —OH Double bond* —H

—OH —OH Double bond* —H —H —OH —OH ═O —H —CO₂C₂H₅ —OH —OH —CH₂OH —H —COH—OH —OH —C₂H₄OH —H —O—CH₃ —OH —OH —CH₃ —H —O—C₂H₅ —OH —OH —C₂H₅ —H —CO₂H—OH —OH —CH═CH₂ —H —OH —OH —OH —CH₂—CH═CH₂ —H —CH₂OH —OH —OH

—H —C₂H₄OH —OH —OH

—H —CH₃ —OH —OH

—H —OH —OH —OH

—H —OH —OH —OH

—H —OH —OH —OH

—H —COOH —OH —OH

—H —CO₂CH₃ —OH —OH

—H —CO₂C₂H₅ —OH —OH

—H —CHO —OH —OH

—H —CH₂OH —OH —OH

—H —CHOHCH₃ —OH —OH

—H —CH₂—CH₂—CH═CH₂ —OH —OH

—H —COOCH₃ —OH —OH

—H —CH₂OCH₃ —OH —OH

—H —CH₂OCH₂CH₃ —OH —OH

—H —CH₂SCH₃ —OH —OH

—H —CH═N—OH —OH —OH

—H

—OH —OH

—H

—OH —OH

—H

—OH —OH

—H

—OH —OH

—H

—OH —OH

—H

—OH —OH

—H

—OH —OH

—H

—OH —OH

—H

—OH —OH

—H

—OH —OH

—H

—OH —OH

—H

—OH —OH

—H *means a double bond between the N atom and the C carbon atom of theN-containing heterocyclic ring of formula I

Example 2 Preparation of Different Compounds According to the Invention

The following example illustrates the preparation of eight derivativesaccording to the invention. These compounds are represented in the tableB below.

TABLE B Compounds according to the invention R₁ R₂ R₃ R₄ R₅2″oxo-voruscharin —COH —OH —OH ═O —H Compound B —CH₂OH —OH —OH ═O —HCompound C —CH₂OAc —OH —OH ═O —H Compound F —CH₂OOCphenyl —OH —OH ═O —HCompound D —CH₂OH —OH —OH Double bond* —H Compound E —CH₂OAc —OH —OHDouble bond* —H Compound G —CH₂OOCphenyl —OH —OH Double bond* —HCompound H —CH₂OH —OH —OH

—H Compound I —CH₂OH —OH —OH

—H *means a double bond between the N atom and the C carbon atom of theN-containing heterocyclic ring of formula I.

2″oxo-voruscharin was isolated from Calotropis procera. First the leafblades, stems, barks and roots of the plant were ground into a finepowder. The powder was then extracted with dichloromethane for at least6, 12, 18 or preferably 24 hours using a soxhlet extractor. Thedichloromethane phase was decanted and filtrated using a fritted glassof porosity no 3. The filtrate was evaporated and a dry extract wasobtained. The dry extract was suspended in hexane and magneticallystirred at room temperature for at least 12 to 16 hours. The suspensionin hexane was then decanted and filtrated with fritted glass of porosityno 3. The insoluble part was then extracted with methanol for at least6, 12 to 16 hours, and the mixture was fitrated with fritted glass ofporosity no 3. The insoluble part of the mixture was then subjected tocolumn chromatography using C18 grafted flash silica gel using a binaryeluent methanol/water in proportion varying from 50:50 to 80:20.

Biological activity was observed in the fractions wherein the binaryeluent proportions were comprised between 60:40 and 70:30. Thesefractions were evaporated to dryness and further subjected to flashchromatography on silica gel using as binary eluentdichloromethane/methanol, which permitted the isolation of two purecompounds: 2″oxo-voruscharin and uscharin.

In order to prepare compound B, 5 eq. of NaBH₄ (7.5 mg, 1.98 10⁻⁴ molwere added to a magnetically stirred solution of 23.9 mg of2″oxo-voruscharin (0.39 10⁻⁴ mol) in 2 ml of methanol. The mixture wasstirred for 1 hour. The solvent was then evaporated under reducedpressure. A flash chromatography on silica gel (CH₂Cl₂; CH₂Cl₂/MeOH:95/5) of the crude product provided 15.9 mg of compound B. The yield ofthis preparation process comprised 66%.

Another derivative consisted of compound C. This compound was preparedby acetylation of compound B, described above. A solution of 3.04 mg ofcompound B (5.0 10⁻⁶ mol) in 1 ml of a mixture 50/50 aceticanhydride/pyridine was stirred for 1 hour 20 minutes at roomtemperature. 1 ml of water was subsequently added at 0° C. understirring. After 15 minutes, the solvent was evaporated under reducedpressure. A flash chromatography on silica gel (CH₂Cl₂/MeOH: 9/1) of thecrude product provided 3.00 mg of compound C. The yield of thispreparation process comprised 92%.

Compound F was prepared by benzoylation of compound B. A solution of10.05 mg of compound B (1.66 10⁻⁵ mole) and 0.5 ml of pyridine wasmagnetically stirred and 5 drops of benzoyl chloride were stirred for 25minutes. The residue was taken up with water and extracted withdichloromethane. After separation, the organic layer was evaporatedunder vacuum. A flash chromatography on silica gel (CH₂Cl₂, CH₂Cl₂/MeOH:99:1, 98:2, 97:3, 96:4) of the crude product provided 8.13 mg ofCompound F. The yield of this preparation process comprised 69%.

The compound D was prepared by adding 5.5 eq. of NaBH₄ (16.8 mg, 4.4410⁻⁴ mol) to a magnetically stirred solution of 47 mg of uscharin (0.8010⁻⁴ mol) in 3 ml of methanol. The mixture was stirred for 10 minutes.The solvent was then evaporated under reduced pressure. A flashchromatography on silica gel (CH₂Cl₂; CH₂Cl₂/MeOH: 95:5) of the crudeproduct provided 31.5 mg of compound D. The yield of this preparationprocess comprised 67%.

Another hemisynthetic derivative consisted of compound E. This compoundwas prepared by acetylation of compound D. A solution of 6.09 mg ofcompound D (0.10 10⁻⁴ mol) in 2 ml of a mixture 50/50 aceticanhydride/pyridine was stirred for 2 hours at room temperature. 2 ml ofwater was added at 0° C. under stirring. After 15 minutes, the solventwas evaporated under reduced pressure. A flash chromatography on silicagel (CH₂Cl₂/MeOH: 9/1) of the crude product provided 5.86 mg of compoundE. The yield of this preparation process comprised 90%.

Compound G was prepared by benzoylation of compound D. A solution of15.13 mg of compound D (2.57 10⁻⁵ mole) and 0.5 ml of pyridine wasmagnetically stirred, and 5 drops of benzoyl chloride were stirred for15 minutes. The residue was taken up with water and extract withdichloromethane. After separation, the organic layer was evaporatedunder vacuum. A flash chromatography on silica gel (CH₂Cl₂, CH₂Cl₂/MeOH:9/1) of the crude product provided 12.5 mg of compound G. The yield ofthis preparation process comprised 70%.

Compound H and I were prepared using compound D as a starting materialaccording to scheme 1:

In 2 ml of THF were successively added, 37.3 mg of compound D (589g/mol, 63.3 10⁻⁶ mole) and 30 μl of BF₃.Et₂O (141.9 g/mol, 3 eq). Themixture was stirred at 0° C. under N₂. After 30 minutes, the mixture wascooled to −78° C. A solution of 75.0 mg of1-phenyl-1(trimethylsilyloxy)ethylene (4 eq) in 0.5 ml of THF wasfinally added. The reaction mixture was stirred at −78° C. for 20minutes and then at room temperature for 1 hour. After neutralization ofthe solution with a 1N solution of NaHCO₃, the mixture was extractedwith dichloromethane and the organic layer was evaporated under vacuum.The 2 isomers, compound H and compound I, were isolated by flashchromatography on silica gel (SiO₂, length=20 cm, diameter=1 cm,gradient of elution: CH₂Cl₂, CH₂Cl₂/MeOH 99:1, 98:2). 8.4 mg (709 g/mol)of the pure compound H were obtained (yield=19%) and 3.5 mg (709 g/mol)of compound I were obtained (yield=8%). In addition, 3.3 mg (709 g/mol)of a mixture of compounds H and I were isolated (yield=7%). The globalyield of this process was 34% for the 2 isomers. The obtained isomerswere analysed by IR spectroscopy and by proton NMR spectrometry.

Example 3 Effect of Different Compounds According to the Invention onOverall Cell Growth of a Cell Line

In order to characterize the in vitro activities of the compoundsaccording to the invention, MTT tests were carried out. The MTT test,which is a well-known test in the art, is an indirect technique thatrapidly measures, i.e. within 5 days, the effect of a given product onthe overall cell growth. This test measures the number of metabolicallyactive living cells that are able to transform the MTT product(3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide), havinga yellowish color, to the blue product formazan dye by mitochondrialreduction. The amount of formazan obtained at the end of the experimentis measured with a spectrophotometer and is directly proportional to thenumber of living cells. Determination of the optical density enables aquantitative measurement of the effect of the investigated compounds ascompared to the control condition (untreated cells) and to compare it toother reference compound. In the following examples different compoundsaccording to the invention were tested and compared to the referencecompound being uscharin.

Six human cancer cell lines, described in Table C, were tested in thepresence of compounds according to the invention. These cell linescovered four histological cancer types, being Glioma, colon, lung andbladder cancer. The cells were allowed to grow in 96-well micro wellswith a flat bottom with an amount of 100 μl of cell suspension per wellin reason to 4000 cells/well depending on cell type. Each cell line wasseeded in its own cell culture medium (Table C).

TABLE C Human cancer cell lines and corresponding cell culture mediumused for the MTT experiments Cell ATCC lines code Tissue MediumLiterature Ref. Hs683 HTB-138 Glioma MEM 5% J. Natl. Cancer Inst. 56:serum 843-849, 1976; ibid. 58: 1455-1463, 1977 U-373 MG HTB-17 GliomaMEM 5% Acta Pathol. Microbial. serum Scand. 74: 465-486, 1968 HCT-15CCL-225 Colon MEM 5% Cancer Res. 39: serum 1020-1025, 1979 LoVo CCL-229Colon MEM 5% Exp. Cell Res: 101: serum 414-416, 1976; J. Natl. CancerInst. 61: 75-83, 1978; Cancer Res. 39: 2630-2636, 1979 A549 CCL-185 LungMEM 5% J. Natl. Cancer Inst. 51: serum 1417-1423, 1973; Int. J. Cancer17: 62-70, 1976 J82 HTB-1 Bladder MEM 5% Br. J. Cancer 38: 64-76, serum1978; In Vitro models for cancer research Vol iV. CRC Press, 103-125,1986

After a 24-hour period of incubation at 37° C., the culture medium isreplaced by 100 μl of fresh medium in which the compound to be testedhas been dissolved at different required concentrations. Differentcompounds were tested at 10⁻⁹ M, 5×10⁻⁹ M, 10⁻⁸ M, 5×10⁻⁸ M, 10⁻⁷ M,5×10⁻⁷ M, 10⁻⁶ M, 5×10⁻⁶ M et 10⁻⁵ M. Each experimental condition iscarried out in hexaplicate. The compounds tested are 2″ oxo-voruscharin,and compounds B, C, D, E, H and I represented in Table B above.

After 72 hours of incubation at 37° C. with the compound (experimentalconditions) or without the compound (control condition), the medium wasreplaced by 100 μl MTT at the concentration of 1 mg/ml dissolved inRPMI. The micro wells were subsequently incubated during 3 hours at 37°C. and centrifuged at 400 g during 10 minutes. The MTT was removed andformazan crystals formed, were dissolved in 100 μl DMSO. The micro wellswere shaken for 5 minutes and read on a spectrophotometer at thewavelengths of 570 nm corresponding to the maximum formazan absorbancewavelength, and of 630 nm, which is the background noise wavelength.

For each experimental condition, the mean OD associated with the SEM(standard error of the mean) for each condition (6 wells) wascalculated. The percentage of remaining living cells in comparison withthe control was calculated. Results of these experiments are representedin FIGS. 2 to 8.

FIG. 1 represents the anti-tumor activity of the known compound uscharinon 5 of the 6 tested cell lines (see Table D). The human tumor cell lineissued from bladder (J82) showed a weaker sensitivity to uscharin.

As illustrated on FIG. 2 to 8 the compounds according to the inventionalso exerted an anti-tumor activity for 5 of the 6 tested cell lines.Only the human tumor cell lines issued from bladder presented weakersensitivity to the 6 compounds than the remaining 5 cell lines. Amongthe 7 compounds, the compounds C and E presented the weakest cytotoxicactivity.

The concentration at which the compounds according to the invention kill50% of cell population, i.e. the IC₅₀ value, is represented in Table D.

TABLE D Comparison of the IC₅₀ value of uscharin with that of thecompounds according to the invention Hs683 U-373 HCT-15 LoVo A549 J82uscharin 5 × 10⁻⁹-10⁻⁹ 5 × 10⁻⁸-10⁻⁸ 5 × 10⁻⁸-10⁻⁸ 10⁻⁸-5 × 10⁻⁹ 5 ×10⁻⁸-10⁻⁸ 10⁻⁵-5 × 10⁻⁶ 2″oxo- 5 × 10⁻⁹-10⁻⁹ 5 × 10⁻⁸-10⁻⁸ 5 × 10⁻⁸-10⁻⁸10⁻⁸-5 × 10⁻⁹ 5 × 10⁻⁸-10⁻⁸ >10⁻⁵ voruscharin Compound B 5 × 10⁻⁶-10⁻⁶ 5× 10⁻⁸-10⁻⁸ 5 × 10⁻⁸-10⁻⁸ 5 × 10⁻⁹-10⁻⁹ 10⁻⁸ 10⁻⁵-5 × 10⁻⁶ Compound C 5× 10⁻⁸-10⁻⁸ 5 × 10⁻⁶-10⁻⁶ 5 × 10⁻⁶-10⁻⁶ 5 × 10⁻⁶-10⁻⁶ 5 × 10⁻⁶-10⁻⁶>10⁻⁵ Compound D 5 × 10⁻⁹-10⁻⁹ 5 × 10⁻⁶-10⁻⁶ 5 × 10⁻⁸-10⁻⁸ 5 × 10⁻⁹-10⁻⁹5 × 10⁻⁸-10⁻⁸ 10⁻⁵-5 × 10⁻⁶ Compound E 5 × 10⁻⁶-10⁻⁶ 5 × 10⁻⁶-10⁻⁶ 5 ×10⁻⁶-10⁻⁶ 5 × 10⁻⁶-10⁻⁶ 5 × 10⁻⁶-10⁻⁶ >10⁻⁶ Compound H 5 × 10⁻⁹-10⁻⁹ 5 ×10⁻⁸-10⁻⁸ 5 × 10⁻⁸-10⁻⁸ 5 × 10⁻⁸-10⁻⁸ 5 × 10⁻⁹-10⁻⁹ 5 × 10⁻⁶-10⁻⁶Compound I 5 × 10⁻⁹-10⁻⁹ 5 × 10⁻⁸-10⁻⁸ 5 × 10⁻⁸-10⁻⁸ 5 × 10⁻⁸-10⁻⁸ 5 ×10⁻⁹-10⁻⁹ 5 × 10⁻⁶-10⁻⁶

The IC₅₀ values for uscharin and 2″oxo-voruscharin ranged between 5×10⁻⁸and 10⁻⁹ M depending on the tested cell line except for J82 where theIC₅₀ value ranged between 10⁻⁵ and 5×10⁻⁶ M for uscharin and higher than10⁻⁵ M for 2″oxo-voruscharin (see table D).

The IC₅₀ value of uscharin and 2″oxo-voruscharin were 1000 fold lowerthan the IC₅₀ value of compound B for the cell line Hs683. The growth ofU-373, HCT-15, LoVo, A549 cell lines was affected in the same way byuscharin, 2″oxo-voruscharin and compounds B, D, H and I. Depending onthe cell line, the IC₅₀ value of uscharin and 2″oxo-voruscharin was 100to 1000 fold lower than the IC₅₀ value of compounds C, and E. The J82cell line was the less sensitive than the other tested cell lines.

FIG. 9 compares the cytotoxic activity of uscharin and 2″oxo-voruscharinon 6 cell lines. Both compounds induced a similar anti-tumor effect oneach tested cell line. The J82 (bladder cancer) cell line was lesssensitive than the other cell lines tested. FIG. 10 compares thecytotoxic activity of uscharin, 2″oxo-voruscharin and compounds B, C, D,E, H and I. On Hs683, uscharin and 2″oxo-voruscharin presented astronger activity than compound B. The growth of U-373, HCT-15, LoVo,A549 cell lines was affected in the same way by uscharin,2″oxo-voruscharin and compounds B, D, H and I. The J82 cell line was theless sensitive than the other tested cell lines.

In conclusion, the novel compound 2″ oxo-voruscharin according to theinvention shows dramatic anti-tumor effects on 5 human cancer cell linesassayed in the present experiments. These anti-tumor effectscorresponded to marked decreases in the overall growth of these humancancers models belonging to four representative histological types.

Also the uscharin, 2″ oxo-voruscharin and compounds B, C, D, E, H and Ishow anti-tumor activities.

Example 4 Effect of Different Compounds According to the Invention onCell Kinetics

According to the experiments performed by means of the MTT colorimetricassay described in example 2, it is clear that the compounds accordingto the invention decrease the overall growth of most of the human cancercell lines submitted to the MTT assay. In the following example theeffect of the compound 2″ oxo-voruscharin according to the invention oncell kinetics was tested and compared to the effect of the knowncompound uscharin.

Cell lines were seeded in flasks (25 cm² area) containing 7 ml ofculture medium. After 48 hours incubation at 37° C. the cell culturemedium was replaced by a fresh medium in which the substance to betested had been dissolved at the different concentrations required.Uscharin and 2″ oxo-voruscharin were tested at concentrations, whichkill 50% and 30% of the cell population, represented by the IC₅₀ andIC₃₀ values, respectively. After 24 or 72 hours of treatment the cellswere harvested in suspension, washed in Phosphate Buffer Saline (PBS) at4° C. and permeabilized with 70% ethanol (at 4° C.) overnight at −20° C.The cells were then washed with PBS and incubated with propidium iodidesolution (80 μg/ml) for 30 minutes at 37° C. and afterward at 4° C.overnight. Ribonuclease A (3% V/V) was added to the PI solution to breakdoubled-stranded RNA. The portrait of the cell cycle was established foreach sample. Software incorporated into the flow cytometer was used todefine precisely the percentage of cells in the different cell cyclephases. Each cell cycle phase was reported in terms of peak surface andcalculated as a percentage. The surface of the entire cell cycle was100%. Each experiment was carried out 3 times. The mean percentage ofeach different phase and the standard error of the related mean werecalculated. Each cell cycle phase of a given condition was compared withthe same cell cycle phase of control. The non-treated cells constitutedcontrol.

Uscharin and 2″ oxo-voruscharin are highly toxic to human tumor celllines. The concentrations used in the flow cytometry experiments werechosen in accordance with the MTT results (example 2). Three humancancer cell lines, Hs683, J82, and HCT-15 were tested and doses thatkilled 30 and 50 percent of the cells were applied to investigatewhether uscharin and 2″ oxo-voruscharin promoted an accumulation in oneof the cell cycle phases when the cell cultures were treated for 24 or72 hours with increasing concentrations of the compounds. The IC₅₀ andIC₃₀ values for uscharin and 2″ oxo-voruscharin corresponding to thethree tested cell lines are represented in Table E.

TABLE E IC₅₀ and IC₃₀ values for uscharin and 2″ oxo-voruscharin withrespect to three human cancer cell lines Uscharin 2″oxo-voruscharin Celllines IC₅₀ IC₃₀ IC₅₀ IC₃₀ Hs683 1.7 × 10⁻⁷ M 4.3 × 10⁻⁸ M 1.7 × 10⁻⁷ M8.3 × 10⁻⁹ M J82 4.3 × 10⁻⁶ M 1.7 × 10⁻⁸ M 4.1 × 10⁻⁶ M 1.7 × 10⁻⁶ MHCT-15 4.3 × 10⁻⁸ M 8.5 × 10⁻⁹ M 1.2 × 10⁻⁸ M 4.1 × 10⁻⁹ M

Analysis of Hs683 cells treated with uscharin (FIG. 11) showed anaccumulation of cells in S-phase when the Hs683 were treated withuscharin at 1.7×10⁻⁷ M for 24 and 72 hours. This effect wasstatistically significant. A significant accumulation in G2/M-phase wasobserved when the cells were treated with uscharin at 1.7×10⁻⁷ M for 24hours. 2″Oxo-voruscharin induced an accumulation in G2/M phase at8.3×10⁻⁹ M after 24 hours of treatment and at both concentrations forthe 72 hours-treatment (FIG. 12). These effects were significant.

The analyses of cell cycle of the J82 cells treated with uscharin (FIG.13) showed that, a significant increase in the S-population occurredindependent of the concentrations applied or the timing of treatment.2″oxo-voruscharin induced an increase of S-population only after 72hours of treatment at both concentrations tested (FIG. 14).

The analyses of cell cycle of the HCT-15 cells treated with uscharin(FIG. 15) and with 2″oxo-voruscharin (FIG. 16) showed that bothcompounds induced an accumulation in S-phase after 72 hours of treatmentat the highest concentration tested respectively 4.3×10⁻⁸ M and 1.2×10⁻⁸M.

The following table F recapitulates the most important effects obtainedwith uscharin and 2″ oxo-voruscharin on the cycle kinetics of the 3 celllines used after 24 and 72 hours-treatment. In conclusion, uscharininduced an accumulation in S-phase in each cell line tested.2″Oxo-voruscharin induced an accumulation in the S phase and in G2/Mphase. These results indicate that uscharin induced more accumulation ofthe cells in the S phase then 2″oxo-voruscharin. Accumulation of cellsin the S phase upon treatment with uscharin indicates that the cellsundergo DNA damage or breaks. Thus, a higher accumulation of cells inthe S phase during uscharin treatment than during 2″oxo-voruscharintreatments indicates that 2″ oxo-voruscharin has a lower toxicity thanuscharin and thus may induce less side-effects on healthy cells.

TABLE F Effects of uscharin and 2″ oxo-voruscharin on the cell cyclekinetics of three human cancer cell lines Cell uscharin 2″oxo-voruscharin lines Time G0/G1 S G2/M G0/G1 S G2/M Hs683 24 h n.s. ****** n.s. n.s. *** 72 h n.s. *** n.s. n.s. n.s. ** J82 24 h n.s. *** n.s.n.s. n.s. n.s. 72 h n.s. *** n.s. n.s. ** n.s. HCT-15 24 h n.s. n.s.n.s. n.s. n.s. n.s. 72 h n.s. ** n.s. n.s. *** n.s. Where n.s. means nosignificant; ** means highly significant; *** very highly significant

Example 5 Determination of the Maximum Tolerated Dose for the CompoundsAccording to the Present Invention

The Maximum Tolerated Dose (MTD) of a given drug is defined as themaximum amount of a drug which can be administered acutely (i.e. in onei.p., i.v., s.c. or per os single dose) to healthy animals, i.e. animalsnot grafted with tumors. The survival times and weights of the animalsare recorded up to 14 days post-injection. Five different doses of eachdrug are used for the determination of the MTD index. When the MTD indexis higher than 160 mg/kg (i.p. administration) the drug is usuallyconsidered to be non-toxic, and the highest dose administered totumor-bearing mice is MTD/2=80 mg/kg. Each experimental group wascomposed of 3 mice for the determination of the MTD index.

The MTD index was measured for 2″ oxo-voruscharin, compound B, compoundC, compound D, compound H and compound I. The MTD index measured for asingle administration in mice of these compounds were 20 mg/kg for 2″oxo-voruscharin, 80 mg/kg for compound B, superior to 40 mg/kg forcompound C, 10 mg/kg for compound D, 80 mg/kg for compound H and 80mg/kg for compound I.

Example 6 Determination of the In Vivo Anti-tumor Pharmacology for theCompounds According to the Present Invention

Three types of results were obtained with in vivo ant-tumorpharmacology: 1) the cumulative toxicity of chemotherapeuticadministrations through recording the weights of the tumor-bearing miceduring treatment, 2) the actual anti-tumor effect exerted at tumorgrowth level. If the tumor models are grafted subcutaneously (s.c.),tumor size is measured three times a week by means of a caliper andexpressed as an area (mm²) by multiplying together the two largestperpendicular diameters, and 3) the gain in survival for the animalstreated, which is evaluated by means of the T/C index. This index is theratio between the median survival time of the group of treated animals(T) and that of the control group. The drug is considered to be activeif the T/C value is above 130% (P<0.05), and toxic for a value lowerthan 70%.

The antitumoral activity of compound B was evaluated in differentxenografted models: sub-cutanous model: MCF-7-TD5 (breast cancer) andC32 (melanoma cancer) and orthotopic model: A549 (lung cancer).

a. Breast Cancer Model:

The MCF-7-TD5 model described herein is a hormono-sensitive form ofMCF-7 transfected with v-Ha-ras oncogene and with a neomycin-resistancegene. Compound B was assayed at MTD/8 (10 mg/kg) and MTD/16 (5 mg/kg)five times a week.

Addition of oestradiol to the growth medium did not increase theproliferation rate of MCF-7-TD5 in vitro, while it produced asignificant stimulation of the parental cells (Int. J. Cancer, 46,522-532 (1990)). After s.c. injection of MCF-7-TD5 into untreated femalenu/nu mice, the MCF-7 TD5 produced tumors after latency periods of 7 to18 weeks. Treatment of mice with additional oestradiol resulted in adrastic shortening of the latency period and in a more rapid tumorgrowth. No oestradiol was used during the experiments described in thisexample.

FIG. 17 shows that 60 administrations of 10 mg/kg and 5 mg/kg ofcompound B significantly decreased MCF-7-TD5 tumor growth but thiseffect was not sufficient to significantly increase the survival periodsof the MCF-7-TD5 tumor bearing mice. FIG. 18 indicates that theadministration schedule of compound B used in the present experimentinduced no major toxic-side effects since the MCF-7-TD5 tumor bearingmice did not lose any significant weight during constant compound Badministrations. On the FIGS. 17 to 22, ↑Mx or ↓Mx refers to the daywhere the median mouse dies in each experiment.

Compound B exerts a significant anti-tumor effect on the MCF-7-TD5breast cancer model without significant side-effects.

b. Melanoma Cancer Model

Experimental melanomas were set up in mice by painting their skins witha carcinogen. These experimental melanomas display certain morphologicalcharacteristics close to, those of human melanomas but are lessaggressive biologically. Compound B was assayed at DMT/4 (20 mg/kg),DMT/8 (10 mg/kg) and DMT/16 (5 mg/kg) three times a week. Compound B at25×20 mg/kg, 28×10 mg/kg and 21×5 mg/kg administration schedules did notsignificantly increase the survival periods of the C32 lungcancer-bearing mice. Indeed the T/C index values measured wererespectively 95%, 107% and 81%.

FIGS. 19 and 20 indicate that the administration schedule of compound Bused in the present experiment decreased the tumor area and did notinduced any major toxic-side effects since the C32-tumor bearing micedid not loose any significant weight during constant administration ofcompound B. The most important effect was obtained with anadministration schedule of 10 mg/kg.

Compound B therefore exerts a significant anti-tumor effect on the C32melanoma cancer model by decreasing the tumor area.

c. Lung Cancer Model

Lung cancer is the leading cause of cancer deaths worldwide. Mostpatients die of progressive metastatic disease despite aggressive localand systemic therapies. The pathogenesis of lung cancer remains highlyelusive due to its aggressive biologic nature and considerableheterogeneity, as compared to other cancers. Orthotopic lung cancermodels are described in the literature using endobronchial,intrathoracic or intravenous injection of tumor cell suspensions and bysurgical implantation of fresh tumor tissue. The tumor cells aredirectly injected into the lung of nude mice. The advantages oforthotopic models include improved tumor take and enhanced invasive andmetastatic properties.

Compound B was assayed at DMT/2 (40 mg/kg), DMT/4 (20 mg/kg) and DMT/8(10 mg/kg) three times a week. Compound B at 3×40 mg/kg administrationschedule did not significantly increase the survival periods of the A549lung cancer-bearing mice following the analysis of the T/C index forwhich the value was 124%. In contrast, when compound B was administratedat 7×20 mg/kg and 10×10 mg/kg, the T/C indexes were respectively of 152%and 186%. These values are statistically significant.

FIG. 21 represents the death rate of nine mice in each of the controland test groups during the experiment. Kaplan-Meier statistical analysiswas used. The statistics value underlines the general fit of the testcontrol in comparison with the general fit of the control group. As itcan be seen from FIG. 22, whatever the used dose in this experiment,compound B significantly prolong the survival of the mice as compared tothe untreated mice. The level significance was p<0.05.

FIG. 22 indicates that compound B administration schedule used in thepresent experiment did not induce any major toxic-side effects since theA549-tumor bearing mice did not lose any significant weight duringconstant compound B administrations, except during the first week ofadministration at 40 mg/kg where a significant loss of weight wasobserved.

Compound B exerts a significant anti-tumor effect on the A549 lungcancer, model by increasing significantly the survival period.

In conclusion, compound B has a significant anti-tumor effect on all themodels used in the current series of experiments. These models representa panel of histological tumor types, including breast cancer, lungcancer and melanomas. These models are clinically relevant because theymimic specific clinical stages of human cancers.

1. A compound of the formula I or a pharmaceutically acceptable saltthereof,

wherein R¹ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl,alkyloxycarbonyl, alkylthiocarbonyl, alkanoyl, cycloalkylalkyl,cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkyithiocarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkoxythiocarbonyl,cycloalkylthioalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl,cycloalkylcarbonyloxyalkyl, silyloxyalkyl, aralkyl, arylalkenyl,arylcarbonyl, aryloxycarbonyl, arylthiocarbonyl, aralkoxycarbonyl,arylalkylthiocarbonyl, aryloxyalkyl, arylthioalkyl, haloalkyl,hydroxyalkyl, aralkanoyl, aroyl, aryloxycarbonylalkyl, aryloxyalkanoyl,carboxyl, formyl, alkenylcarbonyl, alkynylcarbonyl, Het¹, Het¹alkyl,Het¹oxyalkyl, Het¹aryl, Het¹aralkyl, Het¹cycloalkyl, Het¹carbonyl,Het¹alkoxycarbonyl, Het¹alkylthiocarbonyl, Het¹oxycarbonyl,Het¹thiocarbonyl, Het¹alkanoyl, Het¹aralkanoyl, Het¹aryloxyalkyl,Het¹alkyloxyalkyl, Het¹arylthioalkyl, Het¹aryloxycarbonyl,Het¹aralkoxycarbonyl, Het¹aroyl, Het¹oxyalkylcarbonyl,Het¹alkyloxyalkylcarbonyl, Het¹aryloxyalkylcarbonyl,Het¹carbonyloxyalkyl, Het¹alkylcarbonyloxyalkyl,Het¹aralkylcarbonyloxyalkyl, Het²alkyl; Het²oxyalkyl, Het²alkyloxyalkyl,Het²aralkyl, Het²carbonyl, Het²oxycarbonyl, Het²thiocarbonyl,Het²alkanoyl, Het²alkylthiocarbonyl, Het²alkoxycarbonyl, Het²aralkanoyl,Het²aralkoxycarbonyl, Het²aryloxycarbonyl, Het²aroyl, Het²aryloxyalkyl,Het²arylthioalkyl, Het²oxyalkylcarbonyl, Het²alkyloxyalkylcarbonyl,Het²aryloxyalkylcarbonyl, Het²carbonyloxyalkyl,Het²alkylcarbonyloxyalkyl, Het²aralkylcarbonyloxyalkyl, cyano,aminocarbonyl, aminoalkanoyl, aminoalkyl, CR⁶═NR⁷ and CR⁶═N(OR⁷), withR⁶ and R⁷ being independently selected from the group consisting ofhydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,alkynyl, amino alkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino,alkylthiocarbonylamino and arylthiocarbonylamino; wherein R² and R³ areindependently selected from the group consisting of hydroxyl, alkyloxy,alkylsilyloxy, arylsilyloxy, alkyloxyalkyloxy, cycloalkyloxycycloalkylalkyloxy, aralkyloxy, aryloxyalkyloxy, silyloxy,alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy, haloalkyloxy,hydroxyalkyloxy, aralkanoyloxy, aroyloxy, aryloxycarbonylalkyloxy,formyloxy, Het¹alkyloxy, Het¹oxy, Het¹oxyalkyloxy, Het¹aryloxy,Het¹aralkyloxy, Het¹cycloalkyloxy, Het¹carbonyloxy, Het¹oxycarbonyloxy,Het¹alkanoyloxy, Het¹aralkanoyloxy, Het¹aryloxyalkyloxy, Het¹aroyl,Het²oxy, Het²alkyloxy; Het²oxyalkyloxy, Het²aralkyloxy,Het²cycloalkyloxy, Het²alkanoyloxy, Het²aralkanoyloxy, Het²carbonyloxyl,Het²aryloxy, and Het²aryloxyalkyloxy, wherein R¹ R² and R³ areunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, aralkyl, aryl, Het¹, Het²,cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy, cyano,halogen and amino, unsubstituted, mono- or disubstituted wherein thesubstituents are independently selected from the group consisting ofalkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino,arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio,arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio,Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸, SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN,CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂, NR^(8R) ⁹, N(OH)R⁸, C(O)R⁸,C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁶R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸,NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹,NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂NHR⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, andP(O)(OR⁸)(OR⁹), with t being an integer between 1 and 2, and R⁸ R⁹ andR¹⁰ being each independently selected from the group consisting ofhydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,alkynyl, aminoalkyl, amino aryl, alkylcarbonylamino, arylcarbonylamino,alkylthiocarbonylamino and arylthiocarbonylamino; wherein R⁴ is selectedfrom the group consisting of oxo, hydroxyl, alkyl, alkenyl, alkynyl,alkanediyl, alkyloxy, alklylthio, alkylamino, alkyloxyalkyl,arylcarbonylalkyl, alkylcarbonylalkyl, alkanoyl,cycloalkylcarbonylalkyl, cycloalkyl, cycloalkyloxy, cycloalkylthio,cycloalkylamino, cycloalkylalkyl, cycloalkylalkanoyl, aryl, aralkyl,arylalkenyl, arylcarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aryloxyalkyl, haloalkyloxy, haloalkylthio, haloalkylamino ,hydroxyalkyl, aralkanoyl, aryloxycarbonylalkyl, aryloxyalkanoyl, Het¹,Het¹alkyl, Het¹oxy, Het¹oxyalkyl, Het¹aryl, Het¹aralkyl, Het¹cycloalkyl,Het¹aryloxyalkyl, Het¹aroyl, Het², Het²oxy, Het²alkyl; Het²oxyalkyl,Het²aralkyl, Het²cycloalkyl, Het²aryl, Het²alkanoyl, Het²aralkanoyl,Het²aroyl, Het²aryloxyalkyl, aminocarbonyl, aminoalkanoyl, andaminoalkyl, unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of alkyl, aralkyl,aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl,mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,cyano, halogen and amino, unsubstituted, mono- or disubstituted whereinthe substituents are independently selected from the group consisting ofalkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino,arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio,arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio,Het²alkylthio, Het¹oxy and Het²oxy, OR¹¹, SR¹¹, SO₂NR^(11R) ¹²,SO₂N(OH)R¹¹, CN, CR¹¹═NR¹², S(O)R¹¹, SO₂R¹¹, CR¹¹═N(OR¹²), N₃, NO₂,NR¹¹R¹², N(OH)R¹¹, C(O)R¹¹, C(S)R¹¹, CO₂R¹¹, C(O)SR¹¹, C(O)NR¹¹R¹²,C(S)NR¹¹R¹², C(O)N(OH)R¹², C(S)N(OH)R¹¹, NR¹¹C(O)R¹², NR¹¹C(S)R¹²,N(OH)C(O)R¹², N(OH)C(S)R¹¹, NR¹¹CO₂R¹², NR¹¹C(O)NR¹²R¹³, andNR¹¹C(S)NR¹²R¹³, N(OH)CO₂R¹¹, NR¹¹C(O)SR¹², N(OH)C(O)NR¹¹R¹²,N(OH)C(S)NR¹¹R¹², NR¹¹C(O)N(OH)R¹², NR¹¹C(S)N(OH)R¹², NR¹¹SO₂R¹²,MHSO₂NR¹¹R¹², NR¹¹SO₂NHR¹², P(O)(OR¹¹)(OR¹²), wherein t is an integerbetween 1 and 2, R¹¹, R¹² and R¹³ are each independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, and alkynyl; andwherein R⁵ is selected from the group consisting of hydrogen, oxo,hydroxyl, alkyl, alkenyl, alkynyl, alkanediyl, alkyloxy, alkyloxyalkyl,arylcarbonylalkyl, alkylcarbonylalkyl, alkanoyl,cycloalkylcarbonylalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkanoyl, aryl, aralkyl, arylalkenyl, arylcarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aryloxyalkyl, halo alkyl,hydroxyalkyl, aralkanoyl, aryloxycarbonylalkyl, aryloxyalkanoyl, Het¹,Het¹alkyl, Het¹oxy, Het¹oxyalkyl, Het¹aryl, Het¹aralkyl, Het¹cycloalkyl,Het¹aryloxyalkyl, Het¹aroyl, Het², Het²oxy, Het²alkyl; Het²oxyalkyl,Het²aralkyl, Het²cycloalkyl, Het²aryl, Het²alkanoyl, Het²aralkanoyl,Het²aroyl, Het²aryloxyalkyl, aminocarbonyl, amino alkanoyl, and aminoalkyl, unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of alkyl, aralkyl,aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl,mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,cyano, halogen and amino, unsubstituted, mono- or disubstituted whereinthe substituents are independently selected from the group consisting ofalkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,aylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino,arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio,arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio,Het²alkylthio, Het¹oxy and Het²oxy, OR¹¹, SR¹¹, SO₂NR¹¹R¹², SO₂N(OH)R¹¹,CN, CR¹¹═NR¹², S(O)R¹¹, SO₂R¹¹, CR¹¹═N(OR¹²), N₃, NO₂, NR¹¹R¹²,N(OH)R¹¹, C(O)R¹¹, C(S)R¹¹, CO₂R¹¹, C(O)SR¹¹, C(O)NR¹¹R¹², C(S)NR¹¹R¹²,C(O)N(OH)R¹², C(S)N(OH)R¹¹, NR¹¹C(O)R¹², NR¹¹C(S)R¹², N(OH)C(O)R¹²,N(OH)C(S)R¹¹, NR¹¹CO₂R¹², NR¹¹C(O)NR¹²R¹³, and NR¹¹C(S)NR¹²R¹³,N(OH)CO₂R¹¹, NR¹¹C(O)SR¹², N(OH)C(O)NR¹¹R¹², N(OH)C(S)NR¹¹R¹²,NR¹¹C(O)N(OH)R¹², NR¹¹C(S)N(OH)R¹², NR¹¹SO₂R¹², NHSO₂NR¹¹R¹²,NR¹¹SO₂NHR¹², and P(O)(OR¹¹)(OR¹²), wherein t is an integer between 1and 2, R¹¹, R¹² and R¹³ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, and alkynyl; wherein Het¹ isdefined as a saturated or partially unsaturated monocyclic, bicyclic orpolycyclic heterocycle consisting of 3 to 12 ring members which compriseone or more heteroatom ring members selected from nitrogen, oxygen orsulfur, optionally substituted on one or more carbon atoms by alkyl,alkyloxy, halogen, hydroxyl, oxo, optionally mono- or disubstitutedamino, nitro, cyano, haloalkyl, carboxyl, alkoxycarbonyl cycloalkyl,optionally mono- or disubstituted aminocarbonyl, methylthio,methylsulfonyl, aryl and a saturated or partially unsaturatedmonocyclic, bicyclic or tricyclic heterocycle consisting of 3 to 12 ringmembers which contain one or more heteroatom ring members selected fromnitrogen, oxygen or sulfur and whereby the optional substituents on anyamino function are independently selected from alkyl, alkyloxy, Het²,Het²alkyl, Het²oxy, Het²oxyalkyl, aryl, aryloxy, aryloxyalkyl, aralkyl,alkyloxycarbonylamino, amino and aminoalkyl whereby each of the aminogroups may optionally be mono- or disubstituted with alkyl; wherein Het²is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycleconsisting of 3 to 12 ring members comprising one or more heteroatomring members selected from nitrogen, oxygen or sulfur and optionallysubstituted on one or more carbon atoms by alkyl, alkyloxy, halogen,hydroxyl, optionally mono- or disubstituted amino, nitro, cyano,haloalkyl, carboxyl, alkoxycarbonyl, cycloalkyl, optionally mono- ordisubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het¹ andan aromatic monocyclic, bicyclic, or tricyclic heterocycle consisting of3 to 12 ring members, whereby the optional substituents on any aminofunction are independently selected from alkyl, alkyloxy, Het¹,Het¹alkyl, Het¹oxy, Het¹oxyalkyl, aryl, aryloxy, aryloxyalkyl, aralkyl,alkyloxycarbonylamino, amino, and amionalkyl whereby each of the aminogroups may optionally be mono- or disubstituted with alkyl.
 2. Acompound according to claim 1, having the formula I or apharmaceutically acceptable salt thereof,

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl, alkyloxycarbonyl,alkylthiocarbonyl, alkanoyl, cycloalkylalkyl, cycloalkylcarbonyl,cycloalkylalkanoyl, cycloalkyithiocarbonyl, cycloalkylalkoxycarbonyl,cycloalkylalkoxythiocarbonyl, cycloalkylthioalkyl,alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl,silyloxyalkyl, aralkyl, arylalkenyl, arylcarbonyl, aryloxycarbonyl,arylthiocarbonyl, aralkoxycarbonyl, arylalkylthiocarbonyl, aryloxyalkyl,arylthioalkyl, haloalkyl, hydroxyalkyl, aralkanoyl, aroyl,aryloxycarbonylalkyl, aryloxyalkanoyl, carboxyl, formyl,alkenylcarbonyl, alkynylcarbonyl, Het¹, Het¹alkyl, Het¹oxyalkyl,Het¹aryl, Het¹aralkyl, Het¹cycloalkyl, Het¹carbonyl, Het¹alkoxycarbonyl,Het¹alkylthiocarbonyl, Het¹oxycarbonyl, Het¹thiocarbonyl, Het¹alkanoyl,Het¹aralkanoyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹aroyl,Het¹oxyalkylcarbonyl, Het¹alkyloxyalkylcarbonyl,Het¹aryloxyalkylcarbonyl, Het¹carbonyloxyalkyl,Het¹alkylcarbonyloxyalkyl, Het¹aralkylcarbonyloxyalkyl, Het²alkyl;Het²oxyalkyl, Het²alkyloxyalkyl, Het²aralkyl, Het²carbonyl,Het²oxycarbonyl, Het²thiocarbonyl, Het²alkanoyl, Het²alkylthiocarbonyl,Het²alkoxycarbonyl, Het²aralkanoyl, Het²aralkoxycarbonyl,Het²aryloxycarbonyl Het²aroyl, Het²aryloxyalkyl, Het²arylthioalkyl,Het²oxyalkylcarbonyl, Het²alkyloxyalkylcarbonyl,Het²aryloxyalkylcarbonyl, Het²carbonyloxyalkyl,Het²alkylcarbonyloxyalkyl, Het²aralkylcarbonyloxyalkyl, cyano,aminocarbonyl, amino alkanoyl, aminoalkyl, CR⁶═NR⁷ and CR⁶═N(OR⁷), withR⁶ and R⁷ being independently selected from the group consisting ofhydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,alkynyl, amino alkyl, amino aryl, alkylcarbonylamino, arylcarbonylamino,alkylthiocarbonylamino and arylthiocarbonylamino; wherein R² and R³ areindependently selected from the group consisting of hydroxyl, alkyloxy,alkylsilyloxy, arylsilyloxy, alkyloxyalkyloxy, cycloalkyloxycycloalkylalkyloxy, aralkyloxy, aryloxyalkyloxy, silyloxy,alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy, halo alkyloxy,hydroxyalkyloxy, aralkanoyloxy, aroyloxy, aryloxycarbonylalkyloxy,formyloxy, Het¹alkyloxy, Het¹oxy, Het¹oxyalkyloxy, Het¹aryloxy,Het¹aralkyloxy, Het¹cycloalkyloxy, Het¹carbonyloxy, Het¹oxycarbonyloxy,Het¹alkanoyloxy, Het¹aralkanoyloxy, Het¹aryloxyalkyloxy, Het¹aroyl,Het²oxy, Het²alkyloxy; Het²oxyalkyloxy, Het²aralkyloxy,Het²cycloalkyloxy, Het²alkanoyloxy, Het²aralkanoyloxy, Het²carbonyloxyl,Het²aryloxy, and Het²aryloxyalkyloxy, wherein R¹ R² and R³ areunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, aralkyl, aryl, Het¹, Het²,cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy, cyano,halogen and amino, unsubstituted, mono- or disubstituted wherein thesubstituents are independently selected from the group consisting ofalkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino,arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio,arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio,Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸, SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN,CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂, NR⁸R⁹, N(OH)R⁸, C(O)R⁸,C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸,NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹,NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, andP(O)(OR⁸)(OR⁹), with t being an integer between 1 and 2, and R⁸ R⁹ andR¹⁰ being each independently selected from the group consisting ofhydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,alkynyl, amino alkyl, amino aryl, alkylcarbonylamino, arylcarbonylamino,alkyithiocarbonylamino and arylthiocarbonylamino; wherein R⁴ is oxo andR⁵ is hydrogen or alkyl.
 3. A compound according to claim 1, wherein R¹is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl,alkenyl, alkynyl, alkyloxyalkyl, alkylthioalkyl, alkyloxycarbonyl,alkanoyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl,cycloalkylalkoxycarbonyl, cycloalkylthioalkyl, alkylcarbonyloxyalkyl,arylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl, silyloxyalkyl,aralkyl, arylalkenyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl,arylthioalkyl, aralkanoyl, aroyl, carboxyl, formyl, alkenylcarbonyl,alkynylcarbonyl, Het¹oxyalkyl, Het¹alkoxycarbonyl, Het¹oxycarbonyl,Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹oxyalkylcarbonyl,Het¹alkyloxyalkylcarbonyl, Het¹aryloxyalkylcarbonyl,Het¹carbonyloxyalkyl, Het¹alkylcarbonyloxyalkyl,Het¹aralkylcarbonyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²oxycarbonyl, Het²alkoxycarbonyl, Het²aralkoxycarbonyl,Het²aryloxycarbonyl, Het²aryloxyalkyl, Het²arylthioalkyl,Het²oxyalkylcarbonyl, Het²alkyloxyalkylcarbonyl,Het²aryloxyalkylcarbonyl, Het²carbonyloxyalkyl,Het²alkylcarbonyloxyalkyl, Het²aralkylcarbonyloxyalkyl, CR⁶═NR⁷, andCR⁶═N(OR⁷), with R⁶ and R⁷ independently selected from the groupconsisting of hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,Het¹aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino,arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino;wherein R² and R³ are independently selected from the group consistingof hydroxyl, alkyloxy, alkyloxyalkyloxy, cycloalkyloxy,cycloalkylalkyloxy, aralkyloxy, aryloxyalkyloxy, silyloxy,alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy,aryloxycarbonylalkyloxy, formyloxy, Het¹alkyloxy, Het¹oxy,Het¹oxyalkyloxy, Het¹aryloxy, Het¹aralkyloxy, Het¹cycloalkyloxy,Het¹carbonyloxy, Het¹alkanoyloxy, Het¹aralkanoyloxy,Het¹aryloxyalkyloxy, Het²oxy, Het²alkyloxy, Het²oxyalkyloxy,Het²aralkyloxy, Het²cycloalkyloxy, Het²alkanoyloxy, Het²aralkanoyloxy,Het²carbonyloxyl, Het²aryloxy, and Het²aryloxyalkyloxy, wherein R¹ R²and R³ are unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of alkyl, aralkyl,aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl,mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,cyano, halogen and amino, unsubstituted, mono- or disubstituted whereinthe substituents are independently selected from the group consisting ofalkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino,arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio,arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio,Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸, SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN,CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂, NR⁸R⁹, N(OH)R⁸, C(O)R⁸,C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸,NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹,NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, andP(O)(OR⁸)(OR⁹), with t being an integer between 1 and 2, and R⁸ R⁹ andR¹⁰ being each independently selected from the group consisting ofhydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino,alkylthiocarbonylamino and arylthiocarbonylamino; and wherein R⁴ isselected from the group consisting of, oxo, hydroxyalkyl, alkyl,alkenyl, alkylcarbonylalkyl, arylcarbonylalkyl and R⁵ is hydrogen, oxo,hydroxyl, hydroxyalkyl, alkyl, alkenyl, alkylcarbonylalkyl,arylcarbonylalkyl.
 4. A compound according to claim 1 or 2, wherein R¹is selected from the group consisting of alkyl, alkenyl, alkynyl,alkyloxyalkyl, alkylthioalkyl, alkyloxycarbonyl, alkanoyl,cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl,cycloalkylalkoxycarbonyl, cycloalkylthioalkyl, alkylcarbonyloxyalkyl,arylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl, silyloxyalkyl,aralkyl, arylalkenyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl,arylthioalkyl, aralkanoyl, aroyl, carboxyl, formyl, alkenylcarbonyl,alkynylcarbonyl, Het¹oxyalkyl, Het¹alkoxycarbonyl, Het¹oxycarbonyl,Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹oxyalkylcarbonyl,Het¹alkyloxyalkylcarbonyl, Het¹aryloxyalkylcarbonyl,Het¹carbonyloxyalkyl, Het¹alkylcarbonyloxyalkyl,Het¹aralkylcarbonyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²oxycarbonyl, Het²alkoxycarbonyl, Het²aralkoxycarbonyl,Het²aryloxycarbonyl, Het²aryloxyalkyl, Het²arylthioalkyl,Het²oxyalkylcarbonyl, Het²alkyloxyalkylcarbonyl,Het²aryloxyalkylcarbonyl, Het²carbonyloxyalkyl,Het²alkylcarbonyloxyalkyl, Het²aralkylcarbonyloxyalkyl, CR⁶═NR⁷, andCR⁶═N(OR⁷), with R⁶ and R⁷ being independently selected from the groupconsisting of hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,Het¹aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino,arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino;wherein R² and R³ are independently selected from the group consistingof hydroxyl, alkyloxy, alkyloxyalkyloxy, cycloalkyloxycycloalkylalkyloxy, aralkyloxy, aryloxyalkyloxy, silyloxy,alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy,aryloxycarbonylalkyloxy, formyloxy, Het¹alkyloxy, Het¹oxy,Het¹oxyalkyloxy, Het¹aryloxy, Het¹aralkyloxy, Het¹cycloalkyloxy,Het¹carbonyloxy, Het¹alkanoyloxy, Het¹aralkanoyloxy,Het¹aryloxyalkyloxy, Het²oxy, Het²alkyloxy; Het²oxyalkyloxy,Het²aralkyloxy, Het²cycloalkyloxy, Het²alkanoyloxy, Het²aralkanoyloxy,Het²carbonyloxyl, Het²aryloxy, and Het²aryloxyalkyloxy, wherein R¹ R²and R³ are unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of alkyl, aralkyl,aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl,mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,cyano, halogen and amino, unsubstituted, mono- or disubstituted whereinthe substituents are independently selected from the group consisting ofalkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino,arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio,arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio,Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸, SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN,CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂, NR⁸R⁹, N(OH)R⁸, C(O)R⁸,C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸,NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹,NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, andP(O)(OR⁸)(OR⁹), with t being an integer between 1 and 2, and R⁸ R⁹ andR¹⁰ being each independently selected from the group consisting ofhydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,alkynyl, amino alkyl, amino aryl, alkylcarbonylamino, arylcarbonylamino,alkylthiocarbonylamino and arylthiocarbonylamino; and wherein R⁴ is oxoand R⁵ is hydrogen or alkyl.
 5. A compound according to claim 1 or 2,wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, alkyloxyalkyl, alkylthioalkyl, alkanoyl, cycloalkylalkyl,cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylthioalkyl,silyloxyalkyl, aralkyl, arylalkenyl, arylcarbonyl, arylthioalkyl,aralkanoyl, aroyl, carboxyl, formyl, alkenylcarbonyl, alkynylcarbonyl,Het¹oxyalkyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,Het¹oxyalkylcarbonyl, Het¹alkyloxyalkylcarbonyl,Het¹aryloxyalkylcarbonyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²aryloxyalkyl, Het²arylthioalkyl, Het²oxyalkylcarbonyl,Het²alkyloxyalkylcarbonyl, Het²aryloxyalkylcarbonyl, CR⁶═NR⁷, andCR⁶═N(OR⁷), with R⁶ and R⁷ being independently selected from the groupconsisting of hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,Het¹aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino,arylcarbonylamino, alkyithiocarbonylamino and arylthiocarbonylamino;wherein R² and R³ are independently selected from the group consistingof hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy,formyloxy, Het¹carbonyloxy, Het¹alkanoyloxy, Het¹aralkanoyloxy,Het²carbonyloxyl, Het²alkanoyloxy, and Het²aralkanoyloxy, wherein R¹ R²and R³ are unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of alkyl, aralkyl,aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl,mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,cyano, halogen and amino, unsubstituted, mono- or disubstituted whereinthe substituents are independently selected from the group consisting ofalkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino,arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio,arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio,Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸, SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN,CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂, NR⁸R⁹, N(OH)R⁸, C(O)R⁸,C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸,NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹,NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, andP(O)(OR⁸)(OR⁹), with t being an integer between 1 and 2, and R⁸ R⁹ andR¹⁰ being each independently selected from the group consisting ofhydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,alkynyl, amino alkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino,alkyithiocarbonylamino and arylthiocarbonylamino; and wherein R⁴ is oxoand R⁵ is hydrogen or alkyl.
 6. A compound according to claims 1 or 2wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, alkyloxyalkyl, alkylthioalkyl, cycloalkylalkyl,cycloalkylthioalkyl, silyloxyalkyl, aralkyl, arylalkenyl, arylthioalkyl,carboxyl, formyl, Het¹oxyalkyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl,Het¹arylthioalkyl, Het²oxyalkyl, Het²alkyloxyalkyl, Het²aryloxyalkyl,and Het²arylthioalkyl, unsubstituted or substituted by one or moresubstituents independently selected from the group consisting of alkyl,aralkyl, aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,alkylS(═O)_(t), hydroxy, cyano, halogen and amino, unsubstituted, mono-or disubstituted wherein the substituents are independently selectedfrom the group consisting of alkyl, aryl, aralkyl, aryloxy, arylamino,arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio,aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino,cycloalkyl, cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl,Het¹amino, Het²amino, Het¹alkylamino, Het²alkylamino, Het¹thio,Het²thio, Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸,SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN, CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂,NR⁸R⁹, N(OH)R⁸, C(O)R⁸, C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹,C(O)N(OH)R⁹, C(S)N(OH)R⁸, NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹,N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰, NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸,NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹, NR⁸C(O)N(OH)R⁹,NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, and P(O)(OR⁸)(OR⁹),with t being an integer between 1 and 2, and R⁸ R⁹ and R¹⁰ being eachindependently selected from the group consisting of hydrogen, hydroxyl,alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl, alkynyl, amino alkyl,aminoaryl, alkylcarbonylamino, arylcarbonylamino, alkyithiocarbonylaminoand arylthiocarbonylamino; wherein R² and R³ are hydroxyl and wherein R⁴is oxo and R⁵ is hydrogen.
 7. A compound according to claims 1 or 2,wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, alkyloxyalkyl, cycloalkylalkyl, silyloxyalkyl, aralkyl,arylalkenyl, carboxyl, formyl, Het¹oxyalkyl, Het¹aryloxyalkyl,Het¹alkyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl, andHet²aryloxyalkyl, unsubstituted or substituted by one or moresubstituents independently selected from the group consisting of alkyl,aralkyl, aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,alkylS(═O)_(t), hydroxy, cyano, halogen and amino, unsubstituted, mono-or disubstituted wherein the substituents are independently selectedfrom the group consisting of alkyl, aryl, aralkyl, aryloxy, arylamino,arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio,aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino,cycloalkyl, cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl,Het¹amino, Het²amino, Het¹alkylamino, Het²alkylamino, Het¹thio,Het²thio, Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸,SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN, CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂,NR⁸R⁹, N(OH)R⁸, C(O)R⁸, C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹,C(O)N(OH)R⁸, C(S)N(OH)R⁸, NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹,N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰, NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸,NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹, NR⁸C(O)N(OH)R⁹,NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, and P(O)(OR⁸)(OR⁹),with t being an integer between 1 and 2, and R⁸ R⁹ and R¹⁰ being eachindependently selected from the group consisting of hydrogen, hydroxyl,alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl, alkynyl, amino alkyl,amino aryl, alkylcarbonylamino, arylcarbonylamino,alkylthiocarbonylamino and arylthiocarbonylamino; wherein R² and R³ arehydroxyl, R⁴ is oxo and R⁵ is hydrogen.
 8. A compound according toclaims 1 or 2, wherein R¹ is selected from the group consisting ofalkyl, carboxyl, formyl; wherein R² and R³ are hydroxyl, and wherein R⁴is oxo and R⁵ is hydrogen.
 9. A compound according to claim 8, whereinR¹ is formyl, R² and R³ are hydroxyl R⁴ is oxo and R⁵ is hydrogen.
 10. Acompound according to claim 1 or 3, wherein R¹ is selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, alkyloxyalkyl,hydroxyalkyl, alkylthioalkyl, alkanoyl, cycloalkylalkyl,cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylthioalkyl,silyloxyalkyl, aralkyl, arylalkenyl, arylcarbonyl, arylthioalkyl,aralkanoyl, aroyl, carboxyl, formyl, alkenylcarbonyl, alkynylcarbonyl,Het¹oxyalkyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,Het¹oxyalkylcarbonyl, Het¹alkyloxyalkylcarbonyl,Het¹aryloxyalkylcarbonyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²aryloxyalkyl, Het²arylthioalkyl, Het²oxyalkylcarbonyl,Het²alkyloxyalkylcarbonyl, Het²aryloxyalkylcarbonyl, CR⁶═NR⁷, andCR⁶═N(OR⁷), with R⁶ and R⁷ being independently selected from the groupconsisting of hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,Het¹aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino,arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino;wherein R² and R³ are independently selected from the group consistingof hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy,formyloxy, Het¹carbonyloxy, Het¹alkanoyloxy, Het¹aralkanoyloxy,Het²carbonyloxyl, Het²alkanoyloxy, and Het²aralkanoyloxy, wherein R¹ R²and R³ are unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of alkyl, aralkyl,aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl,mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,cyano, halogen and amino, unsubstituted, mono- or disubstituted whereinthe substituents are independently selected from the group consisting ofalkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino,arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio,arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio,Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸, SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN,CR⁸═NR⁹, S(O)R⁸, SO₂R⁸CR⁸═N(OR⁹), N₃, NO₂, NR⁸R⁹, N(OH)R⁸, C(O)R⁸,C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸,NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹,NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, andP(O)(OR⁸)(OR⁹), with t being an integer between 1 and 2, and R⁸ R⁹ andR¹⁰ being each independently selected from the group consisting ofhydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino,alkylthiocarbonylamino and arylthiocarbonylamino; and wherein R⁴ is oxo,hydroxyalkyl, alkyl, alkenyl, arylcarbonylaryl, or alkylcarbonylalkyland R⁵ is hydrogen or alkyl.
 11. A compound according to claim 1 or 3,wherein R¹ is hydroxyalkyl, R² and R³ are hydroxyl, R⁴ is oxo and R⁵ ishydrogen.
 12. A compound according to claim 1 or 3, wherein R¹ isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,hydroxyalkyl, alkyloxyalkyl, alkylthioalkyl, cycloalkylalkyl,cycloalkylthioalkyl, silyloxyalkyl, aralkyl, arylalkenyl, arylthioalkyl,carboxyl, formyl, Het¹oxyalkyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl,Het¹arylthioalkyl, Het²oxyalkyl, Het²alkyloxyalkyl, Het²aryloxyalkyl,and Het²arylthioalkyl, unsubstituted or substituted by one or moresubstituents independently selected from the group consisting of alkyl,aralkyl, aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,alkylS(═O)_(t), hydroxy, cyano, halogen and amino, unsubstituted, mono-or disubstituted wherein the substituents are independently selectedfrom the group consisting of alkyl, aryl, aralkyl, aryloxy, arylamino,arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio,aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino,cycloalkyl, cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl,Het¹amino, Het²amino, Het¹alkylamino, Het²alkylamino, Het¹thio,Het²thio, Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸,SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN, CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂,NR⁸R⁹, N(OH)R⁸, C(O)R⁸, C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹,C(O)N(OH)R⁹, C(S)N(OH)R⁸, NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹,N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰, NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸,NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹, NR⁸C(O)N(OH)R⁹,NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, and P(O)(OR⁸)(OR⁹),with t being an integer between 1 and 2, and R⁸ R⁹ and R¹⁰ being eachindependently selected from the group consisting of hydrogen, hydroxyl,alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl, alkynyl, aminoalkyl,aminoaryl, alkylcarbonylamino, arylcarbonylamino, alkyithiocarbonylaminoand arylthiocarbonylamino; wherein R² and R³ are hydroxyl and wherein R⁴is hydroxyalkyl, arylcarbonylalkyl, or alkylcarbonylalkyl and R⁵ ishydrogen.
 13. A compound according to claim 1 or 3, wherein R¹ isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,hydroxyalkyl, alkyloxyalkyl, cycloalkylalkyl, silyloxyalkyl, aralkyl,arylalkenyl, carboxyl, formyl, Het¹oxyalkyl, Het¹aryloxyalkyl,Het¹alkyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl, andHet²aryloxyalkyl, unsubstituted or substituted by one or moresubstituents independently selected from the group consisting of alkyl,aralkyl, aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,alkylS(═O)_(t), hydroxy, cyano, halogen and amino, unsubstituted, mono-or disubstituted wherein the substituents are independently selectedfrom the group consisting of alkyl, aryl, aralkyl, aryloxy, arylamino,arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio,aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino,cycloalkyl, cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl,Het¹amino, Het²amino, Het¹alkylamino, Het²alkylamino, Het¹thio,Het²thio, Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸,SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN, CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂,NR⁸R⁹, N(OH)R⁸, C(O)R⁸, C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹,C(O)N(OH)R⁹, C(S)N(OH)R⁸, NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹,N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰, NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸,NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹, NR⁸C(O)N(OH)R⁹,NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, and P(O)(OR⁸)(OR⁹),with t being an integer between 1 and 2, and R⁸ R⁹ and R¹⁰ being eachindependently selected from the group consisting of hydrogen, hydroxyl,alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl, alkynyl, aminoalkyl,aminoaryl, alkylcarbonylamino, arylcarbonylamino, alkyithiocarbonylaminoand arylthiocarbonylamino; wherein R² and R³ are hydroxyl, R⁴ ishydroxyalkyl, arylcarbonylalkyl, or alkylcarbonylalkyl and R⁵ ishydrogen.
 14. A compound according to claim 1 or 3, wherein R¹ isselected from the group consisting of alkyl, hydroxyalkyl, carboxyl, andformyl; wherein R² and R³ are hydroxyl, and wherein R⁴ isarylcarbonylalkyl and R⁵ is hydrogen.
 15. A compound according to claim14, wherein R¹ is hydroxyalkyl, R² and R³ are hydroxyl, R⁴ isarylcarbonylalkyl and R⁵ is hydrogen.
 16. A compound according to claim15, wherein R¹ is hydroxymethylene, R² and R³ are hydroxyl, R⁴ isphenylcarbonylmethylene and R⁵ is hydrogen.
 17. A compound having theformula Ia or a pharmaceutically acceptable salt or ester thereof,

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, alkyloxyalkyl, alkylthioalkyl, alkyloxycarbonyl, alkanoyl,cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl,cycloalkylalkoxycarbonyl, cycloalkylthioalkyl, alkylcarbonyloxyalkyl,arylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl, silyloxyalkyl,aralkyl, arylalkenyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl,arylthioalkyl, aralkanoyl, aroyl, silyloxyalkyl, carboxyl,alkenylcarbonyl, alkynylcarbonyl, Het¹oxyalkyl, Het¹alkoxycarbonyl,Het¹oxycarbonyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹oxyalkylcarbonyl,Het¹alkyloxyalkylcarbonyl, Het¹aryloxyalkylcarbonyl,Het¹carbonyloxyalkyl, Het¹alkylcarbonyloxyalkyl,Het¹aralkylcarbonyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²oxycarbonyl, Het²alkoxycarbonyl, Het²aralkoxycarbonyl,Het²aryloxycarbonyl, Het²aryloxyalkyl, Het²arylthioalkyl,Het²oxyalkylcarbonyl, Het²alkyloxyalkylcarbonyl,Het²aryloxyalkylcarbonyl, Het²carbonyloxyalkyl,Het²alkylcarbonyloxyalkyl, Het²aralkylcarbonyloxyalkyl, CR⁶═NR⁷, andCR⁶═N(OR⁷), with R⁶ and R⁷ being independently selected from the groupconsisting of hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,Het¹aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino,arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino;wherein R² and R³ are independently selected from the group consistingof hydroxyl, alkyloxy, alkylsilyloxy, arylsilyloxy, alkyloxyalkyloxy,cycloalkyloxy cycloalkylalkyloxy, aralkyloxy, aryloxyalkyloxy, silyloxy,alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy, haloalkyloxy,hydroxyalkyloxy, aralkanoyloxy, aroyloxy, aryloxycarbonylalkyloxy,formyloxy, Het¹alkyloxy, Het oxy, Het oxyalkyloxy, Het¹aryloxy,Het¹aralkyloxy, Het¹cycloalkyloxy, Het¹carbonyloxy, Het¹oxycarbonyloxy,Het¹alkanoyloxy, Het¹aralkanoyloxy, Het¹aryloxyalkyloxy, Het¹aroyl,Het²oxy, Het²alkyloxy; Hetoxyalkyloxy, Het²aralkyloxy,Het²cycloalkyloxy, Het²alkanoyloxy, Het²aralkanoyloxy, Het²carbonyloxyl,Het²aryloxy, and Het²aryloxyalkyloxy; wherein R¹ R² and R³ areunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, aralkyl, aryl, Het¹, Het²,cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy, cyano,halogen and amino, unsubstituted, mono- or disubstituted wherein thesubstituents are independently selected from the group consisting ofalkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino,arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio,arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio,Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸, SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN,CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂, NR⁸R⁹, N(OH)R⁸, C(O)R⁸,C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸,NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹,NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, andP(O)(OR⁸)(OR⁹), with t being an integer between 1 and 2, and R⁸ R⁹ andR¹⁰ being each independently selected from the group consisting ofhydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino,alkyithiocarbonylamino and arylthiocarbonylamino; wherein R⁴ and R⁵ arehydrogen or alkyl; wherein Het¹ is defined as a saturated or partiallyunsaturated monocyclic, bicyclic or polycyclic heterocycle consisting of3 to 12 ring members which comprise one or more heteroatom ring membersselected from nitrogen, oxygen or sulfur, optionally substituted on oneor more carbon atoms by alkyl, alkyloxy, halogen, hydroxyl, oxo,optionally mono- or disubstituted amino, nitro, cyano, haloalkyl,carboxyl, alkoxycarbonyl cycloalkyl, optionally mono- or disubstitutedaminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated orpartially unsaturated monocyclic, bicyclic or tricyclic heterocycleconsisting of 3 to 12 ring members which contain one or more heteroatomring members selected from nitrogen, oxygen or sulfur and whereby theoptional substituents on any amino function are independently selectedfrom alkyl, alkyloxy, Het², Het²alkyl, Het²oxy, Het²oxyalkyl, aryl,aryloxy, aryloxyalkyl, aralkyl, alkyloxycarbonylamino, amino andaminoalkyl whereby each of the amino groups may optionally be mono- ordisubstituted with alkyl; wherein Het² is defined as an aromaticmonocyclic, bicyclic or tricyclic heterocycle consisting of 3 to 12 ringmembers comprising one or more heteroatom ring members selected fromnitrogen, oxygen or sulfur and optionally substituted on one or morecarbon atoms by alkyl, alkyloxy, halogen, hydroxyl, optionally mono- ordisubstituted amino, nitro, cyano, haloalkyl, carboxyl, alkoxycarbonyl,cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio,methylsulfonyl, aryl, Het¹ and an aromatic monocyclic, bicyclic, ortricyclic heterocycle consisting of 3 to 12 ring members, whereby theoptional substituents on any amino function are independently selectedfrom alkyl, alkyloxy, Het¹, Het¹alkyl, Het¹oxy, Het¹oxyalkyl, aryl,aryloxy, aryloxyalkyl, aralkyl, alkyloxycarbonylamino, amino, andamionalkyl whereby each of the amino groups may optionally be mono- ordisubstituted with alkyl.
 18. A compound according to claim 17, whereinR¹ is selected from the group consisting of alkyl, alkenyl, alkynyl,alkyloxyalkyl, alkylthioalkyl, alkanoyl, cycloalkylalkyl,cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylthioalkyl,silyloxyalkyl, aralkyl, arylalkenyl, arylcarbonyl, arylthioalkyl,aralkanoyl, aroyl, silyloxyalkyl, carboxyl, alkenylcarbonyl,alkynylcarbonyl, Het¹oxyalkyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl,Het¹arylthioalkyl, Het¹oxyalkylcarbonyl, Het¹alkyloxyalkylcarbonyl,Het¹aryloxyalkylcarbonyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²aryloxyalkyl, Het²arylthioalkyl, Het²oxyalkylcarbonyl,Het²alkyloxyalkylcarbonyl, Het²aryloxyalkylcarbonyl, CR⁶═NR⁷, andCR⁶═N(OR⁷), with R⁶ and R⁷ being independently selected from the groupconsisting of hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,Het¹aryl, alkenyl, alkynyl, amino alkyl, aminoaryl, alkylcarbonylamino,arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino;wherein R² and R³ are independently selected from the group consistingof hydroxyl, alkyloxy, alkylsilyloxy, arylsilyloxy, alkyloxyalkyloxy,cycloalkyloxy cycloalkylalkyloxy, aralkyloxy, aryloxyalkyloxy, silyloxy,alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy, halo alkyloxy,hydroxyalkyloxy, aralkanoyloxy, aroyloxy, aryloxycarbonylalkyloxy,formyloxy, Het¹alkyloxy, Het¹oxy, Het¹oxyalkyloxy, Het¹aryloxy,Het¹aralkyloxy, Het¹cycloalkyloxy, Het¹carbonyloxy, Het¹oxycarbonyloxy,Het¹alkanoyloxy, Het¹aralkanoyloxy, Het¹aryloxyalkyloxy, Het¹aroyl,Het²oxy, Het²alkyloxy; Het²oxyalkyloxy, Het²aralkyloxy,Het²cycloalkyloxy, Het²alkanoyloxy, Het²aralkanoyloxy, Het²carbonyloxyl,Het²aryloxy, and Het²aryloxyalkyloxy; wherein R¹ R² and R³ areunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, aralkyl, aryl, Het¹, Het²,cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy, cyano,halogen and amino, unsubstituted, mono- or disubstituted wherein thesubstituents are independently selected from the group consisting ofalkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino,arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio,arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio,Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸, SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN,CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂, NR⁸R⁹, N(OH)R⁸, C(O)R⁸,C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸,NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹,NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, andP(O)(OR⁸)(OR⁹), with t being an integer between 1 and 2, and R⁸ R⁹ andR¹⁰ being each independently selected from the group consisting ofhydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,alkynyl, amino alkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino,alkylthiocarbonylamino and arylthiocarbonylamino; and wherein R⁴ and R⁵are hydrogen or alkyl.
 19. A compound according to claim 17 or 18,wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, alkyloxyalkyl, alkylthioalkyl, cycloalkylalkyl,cycloalkylthioalkyl, silyloxyalkyl, aralkyl, arylalkenyl, arylthioalkyl,silyloxyalkyl, carboxyl, Het¹oxyalkyl, Het¹aryloxyalkyl,Het¹alkyloxyalkyl, Het¹arylthioalkyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²aryloxyalkyl, and Het²arylthioalkyl, unsubstituted or substituted byone or more substituents independently selected from the groupconsisting of alkyl, aralkyl, aryl, Het¹, Het², cycloalkyl,alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy, cyano,halogen and amino, unsubstituted, mono- or disubstituted wherein thesubstituents are independently selected from the group consisting ofalkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino,arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio,arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio,Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸, SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN,CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂, NR⁸R⁹, N(OH)R⁸, C(O)R⁸,C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸,NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹,NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, andP(O)(OR⁸)(OR⁹), with t being an integer between 1 and 2, and R⁸ R⁹ andR¹⁰ being each independently selected from the group consisting ofhydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,alkynyl, aminoalkyl, amino aryl, alkylcarbonylamino, arylcarbonylamino,alkyithiocarbonylamino and arylthiocarbonylamino; wherein R² and R³ arehydroxyl and wherein R⁴ and R⁵ are hydrogen or alkyl.
 20. A compoundaccording to claim 17 or 18, wherein R¹ is selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl, cycloalkylalkyl,silyloxyalkyl, aralkyl, arylalkenyl, carboxyl, Het¹oxyalkyl,Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl,and Het²aryloxyalkyl, unsubstituted or substituted by one or moresubstituents independently selected from the group consisting of alkyl,aralkyl, aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,alkylS(═O)_(t), hydroxy, cyano, halogen and amino, unsubstituted, mono-or disubstituted wherein the substituents are independently selectedfrom the group consisting of alkyl, aryl, aralkyl, aryloxy, arylamino,arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio,aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino,cycloalkyl, cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl,Het¹amino, Het²amino, Het¹alkylamino, Het²alkylamino, Het¹thio,Het²thio, Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸,SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN, CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂,NR⁸R⁹, N(OH)R⁸, C(O)R⁸, C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹,C(O)N(OH)R⁹, C(S)N(OH)R⁸, NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹,N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰, NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸,NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹, NR⁸C(S)N(OH)R⁹,NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, and P(O)(OR⁸)(OR⁹),with t being an integer between 1 and 2, and R⁸ R⁹ and R¹⁰ being eachindependently selected from the group consisting of hydrogen, hydroxyl,alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl, alkynyl, amino alkyl,aminoaryl, alkylcarbonylamino, arylcarbonylamino, alkyithiocarbonylaminoand arylthiocarbonylamino; wherein R² and R³ are hydroxyl and wherein R⁴and R⁵ are hydrogen.
 21. A compound having the formula Ib or apharmaceutically acceptable salt or ester thereof,

wherein R¹ is selected from the group consisting of alkenyl, alkynyl,alkyloxyalkyl, alkylthioalkyl, alkyloxycarbonyl, alkanoyl,cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl,cycloalkylalkoxycarbonyl, cycloalkylthioalkyl, alkylcarbonyloxyalkyl,arylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl, silyloxyalkyl,aralkyl, arylalkenyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl,arylthioalkyl, aralkanoyl, aroyl, silyloxyalkyl, carboxyl,alkenylcarbonyl, alkynylcarbonyl, Het¹oxyalkyl, Het¹alkoxycarbonyl,Het¹oxycarbonyl, Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het¹arylthioalkyl,Het¹aryloxycarbonyl, Het¹aralkoxycarbonyl, Het¹oxyalkylcarbonyl,Het¹alkyloxyalkylcarbonyl, Het¹aryloxyalkylcarbonyl,Het¹carbonyloxyalkyl, Het¹alkylcarbonyloxyalkyl,Het¹aralkylcarbonyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl,Het²oxycarbonyl, Het²alkoxycarbonyl, Het²aralkoxycarbonyl,Het²aryloxycarbonyl, Het²aryloxyalkyl, Het²arylthioalkyl,Het²oxyalkylcarbonyl, Het²alkyloxyalkylcarbonyl,Het²aryloxyalkylcarbonyl, Het²carbonyloxyalkyl,Het²alkylcarbonyloxyalkyl, Het²aralkylcarbonyloxyalkyl, CR⁶═NR⁷, andCR⁶═N(OR⁷), with R⁶ and R⁷ being independently selected from the groupconsisting of hydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl,Het¹aryl, alkenyl, alkynyl, aminoalkyl, amino aryl, alkylcarbonylamino,arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino;wherein R¹ is unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of alkyl, aralkyl,aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl,mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)_(t), hydroxy,cyano, halogen and amino, unsubstituted, mono- or disubstituted whereinthe substituents are independently selected from the group consisting ofalkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl,arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy,arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino,arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio,arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl,cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl, Het¹amino, Het²amino,Het¹alkylamino, Het²alkylamino, Het¹thio, Het²thio, Het¹alkylthio,Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸, SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN,CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂, NR⁸R⁹, N(OH)R⁸, C(O)R⁸,C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹, C(O)N(OH)R⁹, C(S)N(OH)R⁸,NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹, N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰,NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸, NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹,NR⁸C(O)N(OH)R⁹, NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, andP(O)(OR⁸)(OR⁹), with t being an integer between 1 and 2, and R⁸ R⁹ andR¹⁰ being each independently selected from the group consisting ofhydrogen, hydroxyl, alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl,alkynyl, amino alkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino,alkylthiocarbonylamino and arylthiocarbonylamino, and wherein R² and R³are hydroxyl and wherein R⁴ is replaced by a double bond between the Natom and the C carbon atom of the N-containing heterocyclic ring offormula Ib; and wherein R⁵ is hydrogen; wherein Het¹ is defined as asaturated or partially unsaturated monocyclic, bicyclic or polycyclicheterocycle consisting of 3 to 12 ring members which comprise one ormore heteroatom ring members selected from nitrogen, oxygen or sulfur,optionally substituted on one or more carbon atoms by alkyl, alkyloxy,halogen, hydroxyl, oxo, optionally mono- or disubstituted amino, nitro,cyano, haloalkyl, carboxyl, alkoxycarbonyl cycloalkyl, optionally mono-or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and asaturated or partially unsaturated monocyclic, bicyclic or tricyclicheterocycle consisting of 3 to 12 ring members which contain one or moreheteroatom ring members selected from nitrogen, oxygen or sulfur andwhereby the optional substituents on any amino function areindependently selected from alkyl, alkyloxy, Het², Het²alkyl, Het²oxy,Het²oxyalkyl, aryl, aryloxy, aryloxyalkyl, aralkyl,alkyloxycarbonylamino, amino and aminoalkyl whereby each of the aminogroups may optionally be mono- or disubstituted with alkyl; wherein Het²is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycleconsisting of 3 to 12 ring members comprising one or more heteroatomring members selected from nitrogen, oxygen or sulfur and optionallysubstituted on one or more carbon atoms by alkyl, alkyloxy, halogen,hydroxyl, optionally mono- or disubstituted amino, nitro, cyano,haloalkyl, carboxyl, alkoxycarbonyl, cycloalkyl, optionally mono- ordisubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het¹ andan aromatic monocyclic, bicyclic, or tricyclic heterocycle consisting of3 to 12 ring members, whereby the optional substituents on any aminofunction are independently selected from alkyl, alkyloxy, Het¹,Het¹alkyl, Het¹oxy, Het¹oxyalkyl, aryl, aryloxy, aryloxyalkyl, aralkyl,alkyloxycarbonylamino, amino, and amionalkyl whereby each of the aminogroups may optionally be mono- or disubstituted with alkyl.
 22. Acompound according to claim 21, wherein R¹ is selected from the groupconsisting of alkenyl, alkynyl, alkyloxyalkyl, cycloalkylalkyl,silyloxyalkyl, aralkyl, arylalkenyl, carboxyl, Het¹oxyalkyl,Het¹aryloxyalkyl, Het¹alkyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl,and Het²aryloxyalkyl, unsubstituted or substituted by one or moresubstituents independently selected from the group consisting of alkyl,aralkyl, aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,alkylS(═O)_(t), hydroxy, cyano, halogen and amino, unsubstituted, mono-or disubstituted wherein the substituents are independently selectedfrom the group consisting of alkyl, aryl, aralkyl, aryloxy, arylamino,arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio,aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino,cycloalkyl, cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl,Het¹amino, Het²amino, Het¹alkylamino, Het²alkylamino, Het¹thio,Het²thio, Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸,SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN, CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂,NR⁸R⁹, N(OH)R⁸, C(O)R⁸, C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹,C(O)N(OH)R⁹, C(S)N(OH)R⁸, NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹,N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰, NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸,NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹, NR⁸C(O)N(OH)R⁹,NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, and P(O)(OR⁸)(OR⁹),with t being an integer between 1 and 2, and R⁸ R⁹ and R¹⁰ being eachindependently selected from the group consisting of hydrogen, hydroxyl,alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl, alkynyl, aminoalkyl,amino aryl, alkylcarbonylamino, arylcarbonylamino,alkylthiocarbonylamino and arylthiocarbonylamino; wherein R² and R³ arehydroxyl and wherein R⁴ and R⁵ are hydrogen.
 23. A compound according toclaim 22, wherein R¹ is selected from the group consisting of alkyl,alkenyl, alkynyl, alkyloxyalkyl, cycloalkylalkyl, silyloxyalkyl,aralkyl, arylalkenyl, carboxyl, Het¹oxyalkyl, Het¹aryloxyalkyl,Het¹alkyloxyalkyl, Het²oxyalkyl, Het²alkyloxyalkyl, andHet²aryloxyalkyl, unsubstituted or substituted by one or moresubstituents independently selected from the group consisting of alkyl,aralkyl, aryl, Het¹, Het², cycloalkyl, alkyloxycarbonyl, carboxyl,aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl,alkylS(═O)_(t), hydroxy, cyano, halogen and amino, unsubstituted, mono-or disubstituted wherein the substituents are independently selectedfrom the group consisting of alkyl, aryl, aralkyl, aryloxy, arylamino,arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino,arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio,aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino,cycloalkyl, cycloalkylalkyl, Het¹, Het², Het¹alkyl, Het²alkyl,Het¹amino, Het²amino, Het¹alkylamino, Het²alkylamino, Het¹thio,Het²thio, Het¹alkylthio, Het²alkylthio, Het¹oxy and Het²oxy, OR⁸, SR⁸,SO₂NR⁸R⁹, SO₂N(OH)R⁸, CN, CR⁸═NR⁹, S(O)R⁸, SO₂R⁸, CR⁸═N(OR⁹), N₃, NO₂,NR⁸R⁹, N(OH)R⁸, C(O)R⁸, C(S)R⁸, CO₂R⁸, C(O)SR⁸, C(O)NR⁸R⁹, C(S)NR⁸R⁹,C(O)N(OH)R⁹, C(S)N(OH)R⁸, NR⁸C(O)R⁹, NR⁸C(S)R⁹, N(OH)C(O)R⁹,N(OH)C(S)R⁸, NR⁸CO₂R⁹, NR⁸C(O)NR⁹R¹⁰, NR⁸C(S)NR⁹R¹⁰, N(OH)CO₂R⁸,NR⁸C(O)SR⁹, N(OH)C(O)NR⁸R⁹, N(OH)C(S)NR⁸R⁹, NR⁸C(O)N(OH)R⁹,NR⁸C(S)N(OH)R⁹, NR⁸SO₂R⁹, NHSO₂NR⁸R⁹, NR⁸SO₂NHR⁹, and P(O)(OR⁸)(OR⁹),with t being an integer between 1 and 2, and R⁸ R⁹ and R¹⁰ being eachindependently selected from the group consisting of hydrogen, hydroxyl,alkyl, aryl, Het¹, Het¹alkyl, Het¹aryl, alkenyl, alkynyl, amino alkyl,amino aryl, alkylcarbonylamino, arylcarbonylamino,alkyithiocarbonylamino and arylthiocarbonylamino, wherein R² and R³ arehydroxyl; wherein R⁴ replaced by a double bond between the N atom andthe C carbon atom of the N-containing heterocyclic ring of formula Ib;and wherein R⁵ is hydrogen.
 24. A pharmaceutical composition comprisinga pharmaceutically acceptable excipient and a therapeutically effectiveamount of a compound according to any one of claims 1, 17 and
 21. 25. Apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a therapeutically effective amount of a compound accordingto claim
 9. 26. A pharmaceutical composition comprising apharmaceutically acceptable excipient and a therapeutically effectiveamount of a compound according to claim
 11. 27. A method of treatingcancer comprising administering a compound according to any one ofclaims 1, 17, and 21 to an individual in need of such treatment, whereinthe cancer is selected from the group consisting of lung cancer, breastcancer, melanoma cancer, glioma, colon cancer, bladder cancer, andprostate cancer.
 28. A method of treating cancer comprisingadministrating to an individual in need of such treatment apharmaceutical composition according to claim 24, wherein the cancer isselected from the group consisting of lung cancer, breast cancer,melanoma cancer, glioma, colon cancer, bladder cancer, and prostatecancer.